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Establishment and characterization of an orthotopic patient-derived Group 3 medulloblastoma model for preclinical drug evaluation
Lund Univ, Dept Clin Sci Lund, Fac Med, Neurosurg, Lund, Sweden..
Karolinska Inst, Dept Women s & Children s Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Karolinska Inst, Dept Women s & Children s Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46366Article in journal (Refereed) Published
Abstract [en]

Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice. Mice developed symptoms of brain tumours with a latency of 17-18 weeks. Neurosphere cultures were re-established and serially transplanted for 3 generations, with a negative correlation between tumour latency and numbers of injected cells. Xenografts replicated the phenotype of the primary tumour, including high degree of clustering in DNA methylation analysis, high proliferation, expression of tumour markers, MYC amplification and elevated MYC expression, and sensitivity to the MYC inhibitor JQ1. Xenografts maintained maintained expression of tumour-derived VEGFA and stromal-derived COX-2. VEGFA, COX-2 and c-Myc are highly expressed in Group 3 compared to other medulloblastoma subgroups, suggesting that these molecules are relevant therapeutic targets in Group 3 medulloblastoma.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, article id 46366
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-322179DOI: 10.1038/srep46366ISI: 000399363300001PubMedID: 28417956OAI: oai:DiVA.org:uu-322179DiVA, id: diva2:1096143
Funder
Swedish Childhood Cancer FoundationSwedish Foundation for Strategic Research Swedish Society of MedicineSwedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2017-05-17 Created: 2017-05-17 Last updated: 2017-05-17Bibliographically approved

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