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Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

Lookup NU author(s): Dr Christopher Carey

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Abstract

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Publication metadata

Author(s): Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, Venteicher AS, Hebert CH, Carey CD, Rodig SJ, Shareef SJ, Najm FJ, vanGalen P, Wakimoto H, Cahill DP, Rich JN, Aster JC, Suvà ML, Patel AP, Bernstein BE

Publication type: Article

Publication status: Published

Journal: Cell Stem Cell

Year: 2017

Volume: 20

Issue: 2

Pages: 233-246

Print publication date: 02/02/2017

Online publication date: 15/12/2016

Acceptance date: 01/11/2016

ISSN (print): 1934-5909

ISSN (electronic): 1875-9777

Publisher: Cell Press

URL: https://doi.org/10.1016/j.stem.2016.11.003

DOI: 10.1016/j.stem.2016.11.003

PubMed id: 27989769

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