Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

Abstract

Summary 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 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. Importantly, 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.

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

“…Our work suggests that NSCLC cells may dynamically express multiple JmjC KDMs, in line with recent similar observations in glioblastoma (Liau et al, 2017). Further, KDMs may have a role in not just survival from the first drug contact, but also in maintaining transcriptional plasticity and increasing epigenetic alterations during the progression towards robust drug resistance.…”

Epigenetic plasticity and the hallmarks of cancer

“…H3K4 demethylases (KDM5) enable lung and melanoma cell lines to evade anti-proliferative therapies by adopting a slow-cycling persister state (72, 73). H3K27 demethylases (KDM6) enable glioblastoma stem cells to tolerate similar drug pressures by regressing to a more ‘primitive’ developmental state (74). KDM4 family enzymes, which demethylate H3K9 and H3K36, are upregulated in many cancer types, where they deregulate heterochromatin, affect replication timing and prime chromosomal copy number alterations (75, 76).…”

“…As discussed above, stress induced by microenvironment and/or therapeutic intervention up-regulates histone demethylases that reshape the chromatin landscape, potentially inducing plasticity and adaptation to therapy (72–74). Microenvironmental hypoxia has been shown to suppress DNA demethylase activity in breast cancer (97).…”

The impact of non-genetic heterogeneity on cancer cell death

“…Direct inhibition of oncogene function, or inhibition of associated proteins in the same pathway, typically kills most cells within the population (Sharma et al 2006). However, a small (0.1–5%) subpopulation of DTPs can often be isolated; this subpopulation tolerates drug exposure without dying for as long as several weeks and produces progeny that revert to the drug-sensitive state if the drug is subsequently removed (Sharma et al 2010; Raha et al 2014; Liau et al 2017). For example, when PC9 non-small cell lung carcinoma cells harbouring an activating epidermal growth factor receptor (EGFR) mutation are treated with the EGFR inhibitor gefitinib at a dose that exceeds its IC 50 by 100 fold, more than 99.5% of all cells are killed.…”