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.
Bibliographical noteFunding Information:
We thank S. Muller-Knapp and the Structural Genomics Consortium (Oxford, UK), Russell Ryan, Nicol? Riggi, and Henry Pelish for helpful discussions. We thank David Sabatini and Kris Wood for Notch1 intracellular domain-pcw107 and William Hahn and David Root for p-DONR223-PDGFRA M260I. B.B.L. is supported by a Jane Coffin Childs Memorial Fund postdoctoral fellowship. C.S. is supported by a European Molecular Biology Organization (EMBO) fellowship (ALTF 654-2014) and a Swiss National Science Foundation fellowship. P.v.G. is supported by an EMBO Fellowship (ALTF 1207-2014). A.P.P. is supported by the NIH/NINDS (R25NS065743). W.A.F. is supported by an American Brain Tumor Association grant. B.E.B. is an American Cancer Society research professor. This research was supported by funds from the Howard Hughes Medical Institute, the National Human Genome Research Institute, the National Cancer Institute (P50CA165962), and the National Brain Tumor Society.
© 2017 Elsevier Inc.
- drug resistance
- histone demethylases
- stem cell