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Cell Rep. 2016 Dec 13;17(11):2994-3009. doi: 10.1016/j.celrep.2016.11.056.

Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition.

Author information

1
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; Clinical Chemistry and Pharmacology, Uppsala University Hospital, 751 85 Uppsala, Sweden. Electronic address: anna.segerman@igp.uu.se.
2
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
3
Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, 751 85 Uppsala, Sweden.
4
Department of Neurosurgery, Uppsala University Hospital, 751 85 Uppsala, Sweden.
5
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; National Veterinary Institute, 750 07 Uppsala, Sweden. Electronic address: bo.segerman@igp.uu.se.
6
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: bengt.westermark@igp.uu.se.

Abstract

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 continuum of 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.

KEYWORDS:

clones; drug; glioma; heterogeneity; intratumoral; mesenchymal; proneural; radiation; resistant; transition

PMID:
27974212
DOI:
10.1016/j.celrep.2016.11.056
[Indexed for MEDLINE]
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