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Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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. Univ Uppsala Hosp, Clin Chem & Pharmacol, S-75185 Uppsala, Sweden..
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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.
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, p. 2994-3009Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

Place, publisher, year, edition, pages
2016. Vol. 17, no 11, p. 2994-3009
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-314416DOI: 10.1016/j.celrep.2016.11.056ISI: 000390894700019OAI: oai:DiVA.org:uu-314416DiVA, id: diva2:1072690
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved

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Segerman, AnnaNiklasson, MiaHaglund, CarolineBergström, TobiasJarvius, MalinXie, YuanHermansson, AnnikaKastemar, MarianneNyberg, FridaBerglund, MalinSundström, MagnusHesselager, GöranUhrbom, LeneGustafsson, MatsLarsson, RolfFryknäs, MårtenWestermark, Bengt
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Neuro-OncologyScience for Life Laboratory, SciLifeLabCancer Pharmacology and Computational MedicineDepartment of Immunology, Genetics and PathologyClinical and experimental pathology
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