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  • 1.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 390Article in journal (Refereed)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

  • 2.
    Allen, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 354, article id 354re3Article in journal (Refereed)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 3.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, no 10, p. 1690-1698Article, review/survey (Refereed)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

  • 4. Attarha, Sanaz
    et al.
    Roy, Ananya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation2017In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, p. 81-92Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.

  • 5.
    Babateen, Omar M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 100-100, article id P74Article in journal (Other academic)
  • 6.
    Barash, Uri
    et al.
    Rappaport Fac Med, TICC, Haifa, Israel.
    Spyrou, Argyris
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Liu, Pei
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Vlodaysky, Euvgeni
    Rambam Hlth Care Campus, Dept Pathol, Haifa, Israel.
    Zhu, Chenchen
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Luo, Juanjuan
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Su, Dongsheng
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Ilhan, Neta
    Rappaport Fac Med, TICC, Haifa, Israel.
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vlodaysky, Israel
    Rappaport Fac Med, TICC, Haifa, Israel.
    Yang, Xiaojun
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Heparanase promotes glioma progression via enhancing CD24 expression2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1596-1608Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

  • 7.
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    New Molecular Approaches to Glioblastoma Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma (GBM) is the most common high-grade brain tumor diagnosed in patients who are more than 50 years of age. The standard of care treatment is surgery, followed by radiotherapy and chemotherapy. The median life expectancy of patients is only between 12 to 15 months after receiving current treatment regimes. Hence, identification of new therapeutic compounds and gene targets are highly warranted. This thesis describes four interlinked studies to attain this goal. In study 1, we explored drug combination effects in a material of 41 patient-derived GBM cell (GC) cultures. Synergies between three compounds, pterostilbene, gefitinib, and sertraline, resulted in effective killing of GC and can be predicted by biomarkers. In study 2, we performed a large-scale screening of FDA approved compounds (n=1544) in a larger panel of GCs (n=106). By combining the large-scale drug response data with GCs genomics data, we built a novel computational model to predict the sensitivity of each compound for a given GC. A notable finding was that GCs respond very differently to proteasome inhibitors in both in-vitro and in-vivo. In study 3, we explored new gene targets by RNAi (n=1112) in a panel of GC cells. We found that loss of transcription factor ZBTB16/PLZF inhibits GC cell viability, proliferation, migration, and invasion. These effects were due to downregulation of c-MYC and Cyclin B1 after the treatment. In study 4, we tested the genomic stability of three GCs upon multiple passaging. Using molecular and mathematical analyses, we showed that the GCs undergo both systematic adaptations and sequential clonal takeovers. Such changes tend to affect a broad spectrum of pathways. Therefore, a systematic analysis of cell culture stability will be essential to make use of primary cells for translational oncology.

    Taken together, these studies deepen our knowledge of the weak points of GBM and provide several targets and biomarkers for further investigation. The work in this thesis can potentially facilitate the development of targeted therapies and result in more accurate tools for patient diagnostics and stratification. 

  • 8.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hansson, Caroline
    Sahlgrenska Cancer Center, University of Gothenburg.
    Spyrou, Argyris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Atienza Párraga, Alba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Martens, Ulf
    Cell screening facility, Science for Life Laboratory Stockholm.
    Häggblad, Maria
    Cell screening facility, Science for Life Laboratory Stockholm.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lundgren, Bo
    Cell screening facility, Science for Life Laboratory Stockholm.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell linesManuscript (preprint) (Other academic)
  • 9.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed)
    Abstract [en]

    Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

    Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

    Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

    Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

  • 10.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicineManuscript (preprint) (Other academic)
  • 11.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative.

    Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma.

    Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells.

    This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.

  • 12.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Borgenvik, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Camilla U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Qi, Jun
    Bradner, James E
    Cho, Yoon-Jae
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastomaArticle in journal (Other academic)
  • 13.
    Bolin, Sara M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lau, Jasmine
    Chen, Justin
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 14.
    Caja, Laia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tzavlaki, Kalliopi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Dadras, Mahsa Shahidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, E-Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hatem, Gad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morén, Anita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Watanabe, Yukihide
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Univ Tsukuba, Dept Expt Pathol, Fac Med, Tsukuba, Ibaraki, Japan.
    Savary, Katia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Reims, UMR CNRS MEDyC 7369, Reims, France.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 19, p. 2515-2531Article in journal (Refereed)
    Abstract [en]

    Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

  • 15.
    Cane, Gaëlle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Jarvis, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Helbring, Irene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Pardell, Katerina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Ebai, Tonge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Koos, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Protein Diagnostics by Proximity Ligation: Combining Multiple Recognition and DNA Amplification for Improved Protein Analyses2017In: Molecular Diagnostics (Third Edition), 2016: Academia Press, 2017, 3, p. 219-231Chapter in book (Refereed)
    Abstract [en]

    Proximity ligation assay (PLA) is a unique method in which single-stranded oligonucleotides are conjugated to affinity binders of proteins, followed by amplification of the signal by DNA polymerization and hybridization of complementary oligonucleotides labeled with fluorogenic or chromogenic readout. Here, a brief overview of the field of protein analysis describes the background and the initial development of the technique for the detection of protein–protein interactions via the proximity probes mentioned. In this context, PLA can constrain the general problem of cross-reactivity in protein detection by affinity binders, by ensuring that only cognate pairs of proximity probes result in a signal. Thereafter, this chapter deals mainly with derivatives methods and their applications, with a particular interest in improved specificity, application to various biological materials, and multiplexing. The method has been applied in situ and in solution, adapted for the detection of posttranslational modifications such as phosphorylation and interactions between proteins and specific DNA sequences, and multiplexed to a certain extent, which illustrates its versatility. A technique free from enzymatic reaction, the hybridization chain reaction, can be considered a cost-effective alternative particularly suitable to molecular diagnostics. Finally, we explore further development toward higher-level multiplexing and sensitivity. At this point it is not clear what level can be achieved by PLA, but the assay is compatible with a wide range of readout, including separate real-time amplification reactions and novel microfluidic read-out platforms.

  • 16.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    de Oliveira, Kelin Goncalves
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Cerezo-Magana, Myriam
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, Biomed Ctr, Clin Prot Sci & Imaging, Dept Biomed Engn, Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics2019In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 144, no 3, p. 477-488Article in journal (Refereed)
    Abstract [en]

    Purpose Glioblastoma multiforme (GBM) is the most common and lethal of primary malignant brain tumors. Hypoxia constitutes a major determining factor for the poor prognosis of high-grade glioma patients, and is known to contribute to the development of treatment resistance. Therefore, new strategies to comprehensively profile and monitor the hypoxic status of gliomas are of high clinical relevance. Here, we have explored how the proteome of secreted extracellular vesicles (EVs) at the global level may reflect hypoxic glioma cells. Methods We have employed shotgun proteomics and label free quantification to profile EVs isolated from human high-grade glioma U87-MG cells cultured at normoxia or hypoxia. Parallel reaction monitoring was used to quantify the identified, hypoxia-associated EV proteins. To determine the potential biological significance of hypoxia-associated proteins, the cumulative Z score of identified EV proteins was compared with GBM subtypes from HGCC and TCGA databases. Results In total, 2928 proteins were identified in EVs, out of which 1654 proteins overlapped with the ExoCarta EV-specific database. We found 1034 proteins in EVs that were unique to the hypoxic status of U87-MG cells. We subsequently identified an EV protein signature, "HYPSIGNATURE", encompassing nine proteins that strongly represented the hypoxic situation and exhibited close proximity to the mesenchymal GBM subtype. Conclusions We propose, for the first time, an EV protein signature that could comprehensively reflect the hypoxic status of high-grade glioma cells. The presented data provide proof-of-concept for targeted proteomic profiling of glioma derived EVs, which should motivate future studies exploring its utility in non-invasive diagnosis and monitoring of brain tumor patients.

  • 17.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Lund Univ, CEBMMS, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Offer, Svenja
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Freyhult, Eva
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pernemalm, Maria
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Lund, Sigrid M.
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark.
    Pedersen, Shona
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark;Aalborg Univ, Fac Clin Med, Aalborg, Denmark.
    Lehtio, Janne
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, CEBMMS, Lund, Sweden;Lund Univ, Dept Biomed Engn, Biomed Ctr, Clin Prot Sci & Imaging, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Englund, Elisabet
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Sundgren, Pia C.
    Lund Univ, Sect Diagnost Radiol, Dept Clin Sci, Lund, Sweden;Lund Univ, Lund BioImaging Ctr, Lund, Sweden;Skane Univ Hosp, Dept Med Imaging & Funct, Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma2019In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 10, p. 3115-3127Article in journal (Refereed)
    Abstract [en]

    Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma. Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82). Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEV(SDC1) originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEV(SDC1) was decreased postoperatively depending on the extent of surgery. Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.

  • 18.
    Chantzi, Efthymia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enarsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    COMBImage2: a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining2019In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, article id 304Article in journal (Refereed)
    Abstract [en]

    Background: Pharmacological treatment of complex diseases using more than two drugs is commonplace in the clinic due to better efficacy, decreased toxicity and reduced risk for developing resistance. However, many of these higher-order treatments have not undergone any detailed preceding in vitro evaluation that could support their therapeutic potential and reveal disease related insights. Despite the increased medical need for discovery and development of higher-order drug combinations, very few reports from systematic large-scale studies along this direction exist. A major reason is lack of computational tools that enable automated design and analysis of exhaustive drug combination experiments, where all possible subsets among a panel of pre-selected drugs have to be evaluated.

    Results: Motivated by this, we developed COMBImage2, a parallel computational framework for higher-order drug combination analysis. COMBImage2 goes far beyond its predecessor COMBImage in many different ways. In particular, it offers automated 384-well plate design, as well as quality control that involves resampling statistics and inter-plate analyses. Moreover, it is equipped with a generic matched filter based object counting method that is currently designed for apoptotic-like cells. Furthermore, apart from higher-order synergy analyses, COMBImage2 introduces a novel data mining approach for identifying interesting temporal response patterns and disentangling higher- from lower- and single-drug effects.COMBImage2 was employed in the context of a small pilot study focused on the CUSP9v4 protocol, which is currently used in the clinic for treatment of recurrent glioblastoma. For the first time, all 246 possible combinations of order 4 or lower of the 9 single drugs consisting the CUSP9v4 cocktail, were evaluated on an in vitro clonal culture of glioma initiating cells.

    Conclusions: COMBImage2 is able to automatically design and robustly analyze exhaustive and in general higher-order drug combination experiments. Such a versatile video microscopy oriented framework is likely to enable, guide and accelerate systematic large-scale drug combination studies not only for cancer but also other diseases.

  • 19.
    Chantzi, Efthymia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala Univ, In Vitro Syst Pharmacol Facil, SciLifeLab Drug Discovery & Dev, Uppsala, Sweden.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    COMBImage: a modular parallel processing framework for pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies2018In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, article id 453Article in journal (Refereed)
    Abstract [en]

    Background: Large-scale pairwise drug combination analysis has lately gained momentum in drug discovery and development projects, mainly due to the employment of advanced experimental-computational pipelines. This is fortunate as drug combinations are often required for successful treatment of complex diseases. Furthermore, most new drugs cannot totally replace the current standard-of-care medication, but rather have to enter clinical use as add-on treatment. However, there is a clear deficiency of computational tools for label-free and temporal image-based drug combination analysis that go beyond the conventional but relatively uninformative end point measurements.

    Results: COMBImage is a fast, modular and instrument independent computational framework for in vitro pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. Jointly with automated analyses of temporal changes in cell morphology and confluence, it performs and displays conventional cell viability and synergy end point analyses. The image processing algorithms are parallelized using Google's MapReduce programming model and optimized with respect to method-specific tuning parameters. COMBImage is shown to process time-lapse microscopy movies from 384-well plates within minutes on a single quad core personal computer.This framework was employed in the context of an ongoing drug discovery and development project focused on glioblastoma multiforme; the most deadly form of brain cancer. Interesting add-on effects of two investigational cytotoxic compounds when combined with vorinostat were revealed on recently established clonal cultures of glioma-initiating cells from patient tumor samples. Therapeutic synergies, when normal astrocytes were used as a toxicity cell model, reinforced the pharmacological interest regarding their potential clinical use.

    Conclusions: COMBImage enables, for the first time, fast and optimized pairwise drug combination analyses of temporal changes in label-free video microscopy movies. Providing this jointly with conventional cell viability based end point analyses, it could help accelerating and guiding any drug discovery and development project, without use of cell labeling and the need to employ a particular live cell imaging instrument.

  • 20.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gallant, Caroline Julie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Flamourakis, Georgios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fredriksson, Simon
    Olink Biosci, S-75237 Uppsala, Sweden..
    Assarsson, Erika
    Olink Biosci, S-75237 Uppsala, Sweden..
    Lundberg, Martin
    Olink Biosci, S-75237 Uppsala, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 380-389Article in journal (Refereed)
    Abstract [en]

    Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment.

  • 21.
    Dijksterhuis, Jacomijn P.
    et al.
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Arthofer, Elisa
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Marinescu, Voichita D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Ponten, Frederik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, S-17177 Stockholm, Sweden..
    Schulte, Gunnar
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden.;Masaryk Univ, Fac Sci, Inst Expt Biol, CS-61137 Brno, Czech Republic..
    High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 339, no 2, p. 280-288Article in journal (Refereed)
    Abstract [en]

    Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.

  • 22.
    Doroszko, Milena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Turku, Inst Biomed, Turku, Finland.
    Chrusciel, Marcin
    Univ Turku, Inst Biomed, Turku, Finland.
    Stelmaszewska, Joanna
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Slezak, Tomasz
    Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
    Anisimowicz, Slawomir
    Ctr Gynecol & Reprod Endocrinol Artemida, Bialystok, Poland.
    Plöckinger, Ursula
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Berlin, Germany.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Berlin, Germany;Charite Univ Med Berlin, Charite Campus Mitte, Dept Clin Endocrinol, Berlin, Germany.
    Bonomi, Marco
    Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy.
    Wolczynski, Slawomir
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Huhtaniemi, Ilpo
    Univ Turku, Inst Biomed, Turku, Finland;Imperial Coll London, Fac Med, Dept Surg & Canc, London, England.
    Toppari, Jorma
    Univ Turku, Inst Biomed, Turku, Finland;Turku Univ Hosp, Dept Pediat, Turku, Finland.
    Rahman, Nafis A.
    Univ Turku, Inst Biomed, Turku, Finland;Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    GnRH antagonist treatment of malignant adrenocortical tumors2019In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 1, p. 103-117Article in journal (Refereed)
    Abstract [en]

    Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse C alpha 1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin a promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

  • 23.
    Ferrucci, Veronica
    et al.
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy.
    de Antonellis, Pasqualino
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Pennino, Francesco Paolo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Asadzadeh, Fatemeh
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Virgilio, Antonella
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    Montanaro, Donatella
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Galeone, Aldo
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    Boffa, Iolanda
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Pisano, Ida
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Scognamiglio, Iolanda
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Navas, Luigi
    Univ Napoli Federico II, Dept Vet Med & Anim Prod, Naples, Italy.
    Diana, Donatella
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Pedone, Emilia
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Gargiulo, Sara
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Gramanzini, Matteo
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Brunetti, Arturo
    CEINGE Biotecnol Avanzate, Naples, Italy;Univ Napoli Federico II, Dipartimento Sci Biomed Avanzate, Naples, Italy.
    Danielson, Laura
    Inst Canc Res, Div Clin Studies, Sutton SM2 5NG, Surrey, England.
    Carotenuto, Marianeve
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Liguori, Lucia
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Verrico, Antonio
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Quaglietta, Lucia
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Errico, Maria Elena
    Osped Santobono Pausilipon, Pathol Unit, Naples, Italy.
    Del Monaco, Valentina
    CEINGE Biotecnol Avanzate, Naples, Italy.
    D'Argenio, Valeria
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Tirone, Felice
    Fdn Santa Lucia, Natl Res Council, Inst Cell Biol & Neurobiol, Genet Control Dev URT, Rome, Italy.
    Mastronuzzi, Angela
    IRCCS Osped Pediat Bambino Gesu, Dipartimento Oncoematol, Rome, Italy.
    Donofrio, Vittoria
    Osped Santobono Pausilipon, Pathol Unit, Naples, Italy.
    Giangaspero, Felice
    Univ Roma La Sapienza, Dipartimento Sci Radiol Oncol & Anatomo Patol, Rome, Italy;IRCCS Neuromed, Pozzilli, Italy.
    Picard, Daniel
    Univ Hosp Dusseldorf, Dept Paediat Oncol Haematol & Clin Immunol, German Canc Consortium DKTK, Dusseldorf, Germany.
    Remke, Marc
    Univ Hosp Dusseldorf, Dept Paediat Oncol Haematol & Clin Immunol, German Canc Consortium DKTK, Dusseldorf, Germany.
    Garzia, Livia
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Daniels, Craig
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Delattre, Olivier
    PSL Res Univ, Inst Curie, Equipe Labellisue Ligue Canc, INSERM,U830, Paris, France.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA.
    Salvatore, Francesco
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Fattorusso, Roberto
    Dipartimento Sci & Tecnol Ambientali, Biol & Farmaceut, Caserta, Italy.
    Chesler, Louis
    Inst Canc Res, Div Clin Studies, Sutton SM2 5NG, Surrey, England.
    Taylor, Michael D.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Cinalli, Giuseppe
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Zollo, Massimo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy;Azienda Osped Univ Federico II, DAI Med Trasfus, Naples, Italy.
    Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio2018In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, no 5, p. 1300-1319Article in journal (Refereed)
    Abstract [en]

    Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

  • 24. Galli, Stephen J
    et al.
    Tsai, Mindy
    Marichal, Thomas
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Reber, Laurent L
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Approaches for analyzing the roles of mast cells and their proteases in vivo2015In: Advances in Immunology, ISSN 0065-2776, E-ISSN 1557-8445, Vol. 126, p. 45-127Article in journal (Refereed)
    Abstract [en]

    The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such "controversial" results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

  • 25.
    Gezelius, E.
    et al.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bendahl, P. O.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    de Oliveira, K. Goncalves
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    Ek, L.
    Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bergman, B.
    Sahlgrens Univ Hosp, Dept Resp Med, SE-41345 Gothenburg, Sweden.
    Sundberg, J.
    Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Strandberg, K.
    Lund Univ, Inst Lab Med, Dept Clin Chem, Inga Marie Nilssons Gata 53, SE-21428 Malmo, Sweden.
    Kraemer, R.
    Heidelberg Univ, Inorgan Chem Inst, Neuenheimer Feld 270, D-60129 Heidelberg, Germany.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN)2019In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 118, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Background: Coagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. Methods: RASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti-factor Xa (anti-FXa) activity assay. Results: Both methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95-1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89-1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence. (C) 2019 The Authors. Published by Elsevier Ltd.

  • 26.
    Gezelius, Emelie
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Biomarkers of venous thromboembolism in cancer: a silent echo from local events?2019In: Biomarkers in Medicine, ISSN 1752-0363, E-ISSN 1752-0371, Vol. 13, no 7, p. 507-509Article in journal (Other academic)
  • 27.
    Giannuzzi, Diana
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Marconato, Laura
    Ctr Oncol Vet, Bologna, Italy.
    Cascione, Luciano
    USI, IOR, Bellinzona, Switzerland;SIB, Lausanne, Switzerland.
    Comazzi, Stefano
    Univ Milan, Dept Vet Med, Milan, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Pegolo, Sara
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Cecchinato, Alessio
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Bertoni, Francesco
    USI, IOR, Bellinzona, Switzerland.
    Aresu, Luca
    Univ Turin, Dept Vet Sci, Turin, Italy.
    Ferraresso, Serena
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Mutational landscape of canine B-cell lymphoma profiled at single nucleotide resolution by RNA-seq2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0215154Article in journal (Refereed)
    Abstract [en]

    The genomic landscape in human B-cell lymphoma has revealed several somatic mutations and potentially relevant germline alterations affecting therapy and prognosis. Also, mutations originally described as somatic aberrations have been shown to confer cancer predisposition when occurring in the germline. The relevance of mutations in canine B-cell lymphoma is scarcely known and gene expression profiling has shown similar molecular signatures among different B-cell histotypes, suggesting other biological mechanisms underlining differences. Here, we present a highly accurate approach to identify single nucleotide variants (SNVs) in RNA-seq data obtained from 62 completely staged canine B-cell lymphomas and 11 normal B-cells used as controls. A customized variant discovery pipeline was applied and SNVs were found in tumors and differentiated for histotype. A number of known and not previously identified SNVs were significantly associated to MAPK signaling pathway, negative regulation of apoptotic process and cell death, B-cell activation, NF-kB and JAK-STAT signaling. Interestingly, no significant genetic fingerprints were found separating diffuse large B-cell lymphoma from indolent lymphomas suggesting that differences of genetic landscape are not the pivotal causative factor of indolent behavior. We also detected several variants in expressed regions of canine B-cell lymphoma and identified SNVs having a direct impact on genes. Using this brand-new approach the consequence of a gene variant is directly associated to expression. Further investigations are in progress to deeply elucidate the mechanisms by which altered genes pathways may drive lymphomagenesis and a higher number of cases is also demanded to confirm this evidence.

  • 28.
    Giannuzzi, Diana
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Marconato, Laura
    Ctr Oncol Vet, Bologna, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Ferraresso, Serena
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Scarselli, Elisa
    Nouscom Srl, Rome, Italy.
    Fariselli, Piero
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Nicosia, Alfredo
    Nouscom AG, Basel, Switzerland;Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy;CEINGE Biotecnol Avanzate Scarl, Naples, Italy.
    Pegolo, Sara
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Leoni, Guido
    Nouscom Srl, Rome, Italy.
    Laganga, Paola
    Ctr Oncol Vet, Bologna, Italy.
    Leone, Vito F.
    Ctr Oncol Vet, Bologna, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Troise, Fulvia
    Nouscom Srl, Rome, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Aresu, Luca
    Univ Turin, Dept Vet Sci, Turin, Italy.
    Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma2019In: Veterinary and Comparative Oncology, ISSN 1476-5810, E-ISSN 1476-5829, Vol. 17, no 3, p. 308-316Article in journal (Refereed)
    Abstract [en]

    Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell-mediated cytotoxicity and several immune-system-related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed.

  • 29.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 30.
    Goroshchuk, Oksana
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Attarha, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Andersson, Sonia
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Mints, Miriam
    Karolinska Inst, S-10401 Stockholm, Sweden..
    PKN1 overexpression as a predictor of poor survival in endometrial cancer2016In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 32, p. 117-117Article in journal (Other academic)
  • 31.
    Heiland, Dieter H.
    et al.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Ferrarese, Roberto
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Claus, Rainer
    Univ Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany..
    Dai, Fangping
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Masilamani, Anie P.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Eva
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Weyerbrock, Astrid
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Teresia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carro, Maria S.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6940-6954Article in journal (Refereed)
    Abstract [en]

    High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

  • 32. Hill, Rebecca M.
    et al.
    Kuijper, Sanne
    Lindsey, Janet C.
    Petrie, Kevin
    Schwalbe, Ed C.
    Barker, Karen
    Boult, Jessica K. R.
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra L.
    Poon, Evon
    Robinson, Simon P.
    Ruddle, Ruth
    Raynaud, Florence I.
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah Leigh
    Crosier, Stephen
    Ellison, David W.
    Wharton, Stephen B.
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Jacques, Thomas S.
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Chesler, Louis
    Clifford, Steven C.
    Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease2015In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 27, no 1, p. 72-84Article in journal (Refereed)
    Abstract [en]

    We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.

  • 33. Hill, Rebecca M.
    et al.
    Kuijper, Sanne
    Lindsey, Janet
    Schwalbe, Ed C.
    Barker, Karen
    Boult, Jessica
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra
    Poon, Evon
    Robinson, Simon
    Ruddle, Ruth
    Raynaud, Florence
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah
    Crosier, Stephen
    Wharton, Stephen
    Jacques, Tom
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Petrie, Kevin
    Weiss, William A.
    Chesler, Louis
    Clifford, Steve
    MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 34.
    Hoffman, Lindsey M.
    et al.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    van Zanten, Sophie E. M. Veldhuijzen
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Colditz, Niclas
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Baugh, Joshua
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Chaney, Brooklyn
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hoffmann, Marion
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Lane, Adam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Fuller, Christine
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Miles, Lili
    Nemours Childrens Hosp, Orlando, FL USA.
    Hawkins, Cynthia
    Hosp Sick Children, Toronto, ON, Canada.
    Bartels, Ute
    Hosp Sick Children, Toronto, ON, Canada.
    Bouffet, Eric
    Hosp Sick Children, Toronto, ON, Canada.
    Goldman, Stewart
    Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA.
    Leary, Sarah
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA.
    Foreman, Nicholas K.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    Packer, Roger
    Childrens Natl Hlth Syst, Washington, DC USA.
    Warren, Katherine E.
    NCI, Bethesda, MD 20892 USA.
    Broniscer, Alberto
    St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA.
    Kieran, Mark W.
    Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA.
    Minturn, Jane
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA;Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
    Comito, Melanie
    Penn State Univ, Hershey, PA USA.
    Broxson, Emmett
    Wright State Univ, Dayton, OH 45435 USA;Childrens Med Ctr, Dayton, OH USA.
    Shih, Chie-Schin
    Indiana Univ, Indianapolis, IN 46204 USA.
    Khatua, Soumen
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Chintagumpala, Murali
    Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA;Baylor Coll Med, Hematol Ctr, Houston, TX 77030 USA.
    Carret, Anne Sophie
    Ctr Hosp Univ St Justine, Montreal, PQ, Canada.
    Escorza, Nancy Yanez
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hassall, Timothy
    Lady Cilento Childrens Hosp, Brisbane, Qld, Australia.
    Ziegler, David S.
    Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia;Univ New South Wales, Sydney, NSW, Australia.
    Gottardo, Nicholas
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Dholaria, Hetal
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Doughman, Renee
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Benesch, Martin
    Med Univ Graz, Graz, Austria.
    Drissi, Rachid
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Nazarian, Javad
    Childrens Natl Med Ctr, Washington, DC 20010 USA.
    Jabado, Nada
    McGill Univ, Montreal, PQ, Canada.
    Boddaert, Nathalie
    Hop Necker Enfants Malad, Paris, France.
    Varlet, Pascale
    Univ Paris V Descartes, Sorbonne Paris Cite, Hop St Anne, Paris, France.
    Giraud, Geraldine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Castel, David
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Puget, Stephanie
    Hop Necker Enfants Malad, Paris, France.
    Jones, Chris
    Inst Canc Res, Sutton, Surrey, England.
    Hulleman, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Modena, Piergiorgio
    St Anna Como Gen Hosp, Como, Italy.
    Giagnacovo, Marzia
    St Anna Como Gen Hosp, Como, Italy.
    Antonelli, Manila
    Sapienza Univ Rome, Rome, Italy.
    Pietsch, Torsten
    Univ Bonn, Med Ctr, Bonn, Germany.
    Gielen, Gerrit H.
    Univ Bonn, Med Ctr, Bonn, Germany.
    Jones, David T. W.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany.
    Sturm, Dominik
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Pfister, Stefan M.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Gerber, Nicolas U.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Grotzer, Michael A.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Pfaff, Elke
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    von Bueren, Andre O.
    Univ Geneva, Geneva, Switzerland;Univ Hosp Geneva, Geneva, Switzerland.
    Hargrave, Darren
    Great Ormond St Hosp Sick Children, London, England.
    Solanki, Guirish A.
    Birmingham Womens & Childrens Hosp, Birmingham, W Midlands, England.
    Cvrlje, Filip Jadrijevic
    Childrens Hosp Zagreb, Zagreb, Croatia.
    Kaspers, Gertjan J. L.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands;Childrens Hosp Zagreb, Zagreb, Croatia.
    Vandertop, William P.
    Acad Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
    Grill, Jacques
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Bailey, Simon
    Royal Victoria Infirm, Great North Childrens Hosp, Victoria Wing, Newcastle Upon Tyne, Tyne & Wear, England.
    Biassoni, Veronica
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Massimino, Maura
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Calmon, Raphael
    Hop Necker Enfants Malad, Paris, France.
    Sanchez, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Bison, Brigitte
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Warmuth-Metz, Monika
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Leach, James
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Jones, Blaise
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    van Vuurden, Dannis G.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Kramm, Christof M.
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Fouladi, Maryam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries2018In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, no 19, p. 1963-1972Article in journal (Refereed)
    Abstract [en]

    Purpose

    Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs).

    Materials and Methods

    Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia.

    Results

    Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration (P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002).

    Conclusion

    We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

  • 35.
    Hutter, Sonja
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modeling and Targeting MYC Genes in Childhood Brain Tumors2017In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 4, article id 107Article, review/survey (Refereed)
    Abstract [en]

    Brain tumors are the second most common group of childhood cancers, accounting for about 20%-25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors.

  • 36.
    Iannaccone, Marco
    et al.
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Martino, Camillo
    Univ Perugia, Dept Vet Med, Via S Costanzo 4, I-06126 Perugia, Italy.
    Giansante, Daniele
    Ist Zooprofilatt Sperimentale Abruzzo & Molise G, I-64100 Campo Boario, Teramo, Italy.
    Ianni, Andrea
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Martino, Giuseppe
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    RNA Sequencing-Based Whole-Transcriptome Analysis of Friesian Cattle Fed with Grape Pomace-Supplemented Diet2018In: Animals, ISSN 2076-2615, E-ISSN 2076-2615, Vol. 8, no 11, article id 188Article in journal (Refereed)
    Abstract [en]

    Grape pomace (GPO), the main by-product of the wine making process, is a rich source of polyphenols with potent antioxidant properties. Recently, GPO has emerged as a potential feed additive in livestock nutrition, with several reports describing its beneficial effects on animals' overall health status or production traits. However, little is known about it from a molecular biology standpoint. In the present study, we report the first RNA sequencing-based whole-transcriptome profiling of Friesian calves fed with a GPO-supplemented diet. We identified 367 differentially expressed genes (p < 0.05) in the GPO-supplemented calves (n = 5), when compared with unsupplemented control group (n = 5). The pathway analysis showed that cholesterol lipid biosynthesis' was the most negatively-enriched (p < 0.001) pathway in the GPO-supplemented animals. In specific terms, five important genes coding for cholesterol biosynthesis enzymes, namely the Farnesyl-diphosphate Farnesyltransferase 1 (FDFT-1), Squalene Epoxidase (SQLE), NAD(P)-dependent Steroid Dehydrogenase-like (NSDHL), Methylsterol Monooxygenase (MSMO)-1, and Sterol-C5-desaturase (SC5D), two major transcription factors (the Sterol Regulatory Element-binding Transcription Factor 1 and 2), as well as the Low-Density Lipoprotein Receptor (LDLR), were all downregulated following GPO supplementation. Such an effect was mirrored by a reduction of blood cholesterol levels (p = 0.07) and a lowered (p < 0.001) Malondialdehyde (lipid oxidation marker) level in carcasses. We provide evidence on the effects of GPO-supplemented diets on the whole-transcriptome signature in veal calves, which mainly reflects an antioxidant activity.

  • 37.
    Jiang, Yiwen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Olofsson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 38.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Large scale integration and interactive exploration of cancer data – with applications to glioblastoma2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glioblastoma is the most common malignant brain tumor, with a median survival of approximately 15 months. The standard of care treatment consists of surgical resection followed by radiotherapy and chemotherapy, where chemotherapy only prolongs survival by approximately 3 months. There is therefore an urgent need for new approaches to better understand the molecular vulnerabilities of glioblastoma. To this end, we have conducted four interdisciplinary studies.

    In study 1 we develop a method for efficiently constructing and exploring large integrative network models that include multiple cohorts and multiple types of molecular data. We apply this method to 8 cancers from The Cancer Genome Atlas (TCGA) and make the integrative network available for exploration and visualization through a custom web interface.

    In study 2 we establish a biobank of 48 patient derived glioblastoma cell cultures called the Human Glioma Cell Culture (HGCC) resource. We show that the HGCC cell cultures represent all transcriptional subtypes, carry genomic aberrations typical of glioblastoma, and initiate tumors in vivo. The HGCC is an open resource for translational glioblastoma research, made available through hgcc.se.

    In study 3 we extend the analysis of HGCC cell cultures both in terms of number (to over 100) and in terms of data types (adding mutation, methylation and drug response data). Large-scale drug profiling starting from over 1500 compounds identified two distinct groups of cell cultures defined by vulnerability to proteasome inhibition, p53/p21 activity, stemness and protein turnover. By applying machine learning methods to the combined drug profiling and matched genomics data we construct a first network of predictive biomarkers.

    In study 4 we use the methods developed in study 1 applied to the data generated in studies 2 and 3 to construct an integrative network model of HGCC and glioblastoma data from TCGA. We present an interactive method for exploring this network based on searching for network patterns representing specific hypotheses defined by the user.

    In conclusion, this thesis combines the development of integrative models with applications to novel data relevant for translational glioblastoma research. This work highlights several potentially therapeutically relevant aspects, and paves a path towards more comprehensive and informative models of glioblastoma.

  • 39.
    Johansson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Exploring large scale integrative networks of glioblastoma using hypothesis driven pattern searchManuscript (preprint) (Other academic)
  • 40.
    Johansson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Schmidt, Linnéa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of Molecular Medicine, Aarhus University, Aarhus, Denmark.
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Gallant, Caroline J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kling, Teresia
    Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, Sweden.
    Awe, Olatilewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of Neurosurgery, University of Iowa, IA, USA.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Holmberg Olausson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Almstedt, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Häggblad, Maria
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Martens, Ulf
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Lundgren, Bo
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Lönnstedt, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Walter and Eliza Hall Institute of Medical Research, Australia.
    Frigault, Melanie M.
    Translational Sciences, Oncology, IMED Biotech Unit, AstraZeneca, Boston, US.
    Hurt, Elaine
    Division of Oncology, Medimmune LLC, Gaithersburg, MD, USA.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Decoding glioblastoma drug responses using an open access library of patient derived cell modelsManuscript (preprint) (Other academic)
  • 41.
    Johansson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Schmidt, Linnéa*
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Department of Molecular Medicine, Aarhus University, Aarhus, Denmark.
    Baskaran, Sathishkumar*
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Gallant, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kling, Teresia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Awe, Olatilewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Department of Neurosurgery, University of Iowa, IA, USA.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Almstedt, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Häggblad, Maria
    Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Martens, Ulf
    Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Lundgren, Bo
    Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Lönnstedt, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Walter and Eliza Hall Institute of Medical Research, Australia.
    Frigault, Melanie
    Translational Science, Acerta Pharma, Redwood City, CA, USA.
    Hurt, Elaine
    Division of Oncology, Medimmune LLC, Gaithersburg, MD, USA.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Targeting tumor heterogeneity: multi-omic modeling of glioblastoma drug response using an open-access library of patient-derived cellsManuscript (preprint) (Other academic)
  • 42.
    Kahn, Suzana A.
    et al.
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Canc Ctr, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA.
    Wang, Xin
    Univ Toronto, Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada.
    Nitta, Ryan T.
    Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Gholamin, Sharareh
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Canc Ctr, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Theruvath, Johanna
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Hutter, Gregor
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Azad, Tej D.
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Wadi, Lina
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Ramaswamy, Vijay
    Univ Toronto, Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada.
    Esparza, Rogelio
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Liu, Kun-Wei
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, 2880 Torrey Pines Scen Dr, La Jolla, CA 92037 USA.
    Edwards, Michael
    Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA.
    Johansson, Fredrik K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sahoo, Debashis
    Univ Calif San Diego, Dept Pediat, San Diego, CA 92093 USA;Univ Calif San Diego, Dept Comp Sci & Engn, San Diego, CA 92093 USA.
    Li, Gordon
    Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA.
    Wechsler-Reya, Robert J.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, 2880 Torrey Pines Scen Dr, La Jolla, CA 92037 USA.
    Reimand, Juri
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada;Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.
    Cho, Yoon-Jae
    Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA.
    Taylor, Michael D.
    Univ Toronto, Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada.
    Weissman, Irving L.
    Stanford Univ, Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Canc Ctr, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA.
    Mitra, Siddhartha S.
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Canc Ctr, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA;Univ Colorado, Sch Med, Childrens Hosp Colorado, Dept Pediat, Room P18-4114,Res Complex 1 North MS 8302, Aurora, CO 80045 USA.
    Cheshier, Samuel H.
    Stanford Univ, Lucile Packard Childrens Hosp, Div Pediat Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Canc Ctr, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Dept Neurosurg, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Ludwig Inst Canc Res, Sch Med, Stanford, CA 94305 USA;Univ Utah, Primary Childrens Hosp, Div Pediat Neurosurg, Dept Neurosurg, 100 North Mario Capecchi Dr Suite 3850, Salt Lake City, UT 84113 USA;Univ Utah, Huntsman Canc Inst, 100 North Mario Capecchi Dr Suite 3850, Salt Lake City, UT 84113 USA.
    Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4121Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

  • 43.
    Karademir, Betul
    et al.
    Marmara Univ, Sch Med, Dept Biochem, Genet & Metab Dis Res & Invest Ctr, Istanbul, Turkey.
    Sari, Gulce
    Marmara Univ, Sch Med, Dept Biochem, Genet & Metab Dis Res & Invest Ctr, Istanbul, Turkey;Okan Univ, Fac Engn, Dept Genet & Bioengn, Istanbul, Turkey.
    Jannuzzi, Ayse Tarbin
    Istanbul Univ, Fac Pharm, Dept Pharmaceut Toxicol, Istanbul, Turkey.
    Musunuri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Grune, Tilman
    German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Toxicol, D-14558 Nuthetal, Germany;German Ctr Diabet Res DZD, D-85764 Munich, Germany;German Ctr Cardiovasc Res DZHK, D-10117 Berlin, Germany.
    Mi, Jia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Binzhou Med Univ, Med & Pharm Res Ctr, Yantai, Peoples R China.
    Hacioglu-Bay, Husniye
    Marmara Univ, Sch Med, Dept Anat, Istanbul, Turkey.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Jung, Tobias
    German Inst Human Nutr Potsdam Rehbruecke DIfE, Dept Mol Toxicol, D-14558 Nuthetal, Germany;German Ctr Diabet Res DZD, D-85764 Munich, Germany;German Ctr Cardiovasc Res DZHK, D-10117 Berlin, Germany.
    Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16318Article in journal (Refereed)
    Abstract [en]

    The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

  • 44.
    Kling, Teresia
    et al.
    Gothenburg Univ, Sahlgrenska Acad, Sahlgrenska Canc Ctr, Inst Biomed,Dept Pathol, S-41124 Gothenburg, Sweden..
    Ferrarese, Roberto
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Ailin, Darren Oh
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Biol, Schnzlestr 1, D-79104 Freiburg, Germany..
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heiland, Dieter Henrik
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Dai, Fangping
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Vasilikos, Ioannis
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Weyerbrock, Astrid
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Jornsten, Rebecka
    Univ Gothenburg, Math Sci, SE-41296 Gothenburg, Sweden.;Chalmers, SE-41296 Gothenburg, Sweden..
    Carro, Maria Stella
    Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma2016In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, p. 72-85Article in journal (Refereed)
    Abstract [en]

    Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.

  • 45.
    Kling, Teresia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sanchez, Jose
    Chalmers, S-41296 Gothenburg, Sweden..
    Marinescu, Voichita D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Uppsala, Sweden..
    Jornsten, Rebecka
    Chalmers, S-41296 Gothenburg, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Efficient exploration of multi-cancer networks by generalized covariance selection and interactive web content2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 22, article id B2-35Article in journal (Other academic)
  • 46.
    Kling, Teresia
    et al.
    Univ Gothenburg, Sahlgrenska Canc Ctr, SE-40530 Gothenburg, Sweden.;Univ Gothenburg, Dept Mol & Clin Med, SE-40530 Gothenburg, Sweden..
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sanchez, Jose
    Univ Gothenburg, Math Sci, SE-41296 Gothenburg, Sweden.;Chalmers, SE-41296 Gothenburg, Sweden..
    Marinescu, Voichita D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jornsten, Rebecka
    Univ Gothenburg, Math Sci, SE-41296 Gothenburg, Sweden.;Chalmers, SE-41296 Gothenburg, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Efficient exploration of pan-cancer networks by generalized covariance selection and interactive web content2015In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 15, article id e98Article in journal (Refereed)
    Abstract [en]

    Statistical network modeling techniques are increasingly important tools to analyze cancer genomics data. However, current tools and resources are not designed to work across multiple diagnoses and technical platforms, thus limiting their applicability to comprehensive pan-cancer datasets such as The Cancer Genome Atlas (TCGA). To address this, we describe a new data driven modeling method, based on generalized Sparse Inverse Covariance Selection (SICS). The method integrates genetic, epigenetic and transcriptional data from multiple cancers, to define links that are present in multiple cancers, a subset of cancers, or a single cancer. It is shown to be statistically robust and effective at detecting direct pathway links in data from TCGA. To facilitate interpretation of the results, we introduce a publicly accessible tool ( ext-link-type="uri" xlink:href="http://cancerlandscapes.org/">cancerlandscapes.org), in which the derived networks are explored as interactive web content, linked to several pathway and pharmacological databases. To evaluate the performance of the method, we constructed a model for eight TCGA cancers, using data from 3900 patients. The model rediscovered known mechanisms and contained interesting predictions. Possible applications include prediction of regulatory relationships, comparison of network modules across multiple forms of cancer and identification of drug targets.

  • 47.
    Kundu, Soumi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    The involvement of heparan sulfate proteoglycans in stem cell differentiation and in malignant glioma2016In: The European Physical Journal Plus, ISSN 2190-5444, E-ISSN 2190-5444, Vol. 131, no 4, article id 85Article, review/survey (Refereed)
    Abstract [en]

    Heparan sulfate (HS) proteoglycans (HSPG) are major components of the extracellular matrix. They interact with a plethora of macromolecules that are of physiological importance. The pattern of sulfation of the HS chain determines the specificity of these interactions. The enzymes that synthesize and degrade HS are thus key regulators of processes ranging from embryonic development to tissue homeostasis and tumor development. Formation of the nervous system is also critically dependent on appropriate HSPGs as shown by several studies on the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common primary malignant brain tumor among adults, and the prognosis is poor. Neural and glioma stem cells share several traits, including sustained proliferation and highly efficient migration in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside and the tumorigenic niche, including their interactions with components of the extracellular matrix (ECM). The levels of many of these components, for example HSPGs and enzymes involved in the biosynthesis and modification of HS are attenuated in gliomas. In this paper, HS regulation of pathways involved in neural differentiation and how these may be of importance for brain development are discussed. The literature suggesting that modifications of HS could regulate glioma growth and invasion is reviewed. Targeting the invasiveness of glioma cells by modulating HS may improve upon present therapeutic options, which only marginally enhance the survival of glioma patients.

  • 48.
    Kundu, Soumi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Spyrou, Argyris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marinescu, Voichita D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ilan, Neta
    Technion, Ruth & Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel.
    Vlodavsky, Israel
    Technion, Ruth & Bruce Rappaport Fac Med, Canc & Vasc Biol Res Ctr, Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heparanase Promotes Glioma Progression and is Inversely Correlated with Patient Survival.2016In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 14, no 12, p. 1243-1253Article in journal (Refereed)
    Abstract [en]

    Malignant glioma continues to be fatal, despite improved insight into its underlying molecular mechanisms. The most malignant form, glioblastoma (GBM), is characterized by aberrant activation of receptor tyrosine kinases (RTK) and infiltrative growth. Heparan sulfate proteoglycans (HSPGs), integral components of the extracellular matrix of brain tumors (HPSE), which cleaves HSPGs, for its role in glioma. This hypothesis was evaluated using tissue microarrays, GBM cells derived from patients, murine in vitro and in vivo can regulate activation of many RTK pathways. This prompted us to investigate heparanase models of glioma, and public databases. Down-regulation of HPSE attenuated glioma cell proliferation, while addition of HPSE stimulated growth, and activated ERK and AKT signaling. Using HPSE transgenic and knockout mice it was demonstrated that tumor development in vivo was positively correlated to HPSE levels in the brain. HPSE also modified the tumor microenvironment, influencing reactive astrocytes, microglia/monocytes and tumor angiogenesis. Furthermore, inhibition of HPSE reduces tumor cell numbers, both in vitro and in vivo. HPSE was highly expressed in human glioma and GBM cell lines, compared to normal brain tissue. Indeed, a correlation was observed between high levels of HPSE and shorter survival of patients with high-grade glioma. In conclusion, these data provide proof-of-concept for anti-HPSE treatment of malignant glioma, as well as novel insights for the development of HPSE as a therapeutic target.

    IMPLICATIONS: This study aims to target both the malignant brain tumor cells per se, and their microenvironment by changing the level of an enzyme, heparanase, that breaks down modified sugar chains on cell surfaces and in the extracellular space.

  • 49.
    Kurylo, Chad M.
    et al.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Parks, Matthew M.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Juette, Manuel F.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Zinshteyn, Boris
    Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA;Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA.
    Altman, Roger B.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Thibado, Jordana K.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Vincent, C. Theresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Blanchard, Scott C.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA;Weill Cornell Med, Triinst Training Program Chem Biol, New York, NY 10065 USA.
    Endogenous rRNA Sequence Variation Can Regulate Stress Response Gene Expression and Phenotype2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 25, no 1, p. 236-248.e6Article in journal (Refereed)
    Abstract [en]

    Prevailing dogma holds that ribosomes are uniform in composition and function. Here, we show that nutrient limitation-induced stress in E. coli changes the relative expression of rDNA operons to alter the rRNA composition within the actively translating ribosome pool. The most upregulated operon encodes the unique 16S rRNA, rrsH, distinguished by conserved sequence variation within the small ribosomal subunit. rrsH-bearing ribosomes affect the expression of functionally coherent gene sets and alter the levels of the RpoS sigma factor, the master regulator of the general stress response. These impacts are associated with phenotypic changes in antibiotic sensitivity, biofilm formation, and cell motility and are regulated by stress response proteins, ReIA and ReIE, as well as the metabolic enzyme and virulence-associated protein, AdhE. These findings establish that endogenously encoded, naturally occurring rRNA sequence variation can modulate ribosome function, central aspects of gene expression regulation, and cellular physiology.

  • 50.
    Lobon-Iglesias, M. J.
    et al.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.
    Castel, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Philippe, C.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Debily, M. A.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Univ Evry Val dEssone, Evry, France..
    Briandet, C.
    Univ Hosp Dijon, Dept Pediat, Dijon, France..
    Fouyssac, F.
    Univ Hosp Nancy Brabois, Dept Pediat Oncol, Nancy, France..
    de Carli, E.
    Univ Hosp Angers, Dept Pediat Oncol, Angers, France..
    Dufour, C.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Valteau-Couanet, D.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France..
    Sainte-Rose, C.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Blauwblomme, T.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Beccaria, K.
    Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France.;Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Zerah, M.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Puget, S.
    Necker Sick Childrens Univ Hosp, Dept Neurosurg, Paris, France.;Paris Descartes Univ, Paris, France..
    Calmon, R.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Boddaert, N.
    Paris Descartes Univ, Paris, France.;Necker Sick Childrens Univ Hosp, Dept Radiol, Paris, France.;Imagine Inst, Paris, France.;INSERM, U1163, Paris, France..
    Bolle, S.
    Gustave Roussy, Dept Radiotherapy, Villejuif, France..
    Varlet, P.
    Paris Descartes Univ, Paris, France.;St Anne Hosp, Dept Neuropathol, Paris, France..
    Grill, J.
    Gustave Roussy, Dept Pediat & Adolescent Oncol, Villejuif, France.;Univ Paris Saclay, Villejuif, France.;CNRS, Unite Mixte Rech 8203, Team Target Identificat & Innovat Anticanc Therap, Villejuif, France..
    Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?2018In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 137, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

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