Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.
Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.
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DOI：
10.1016/j.stem.2016.11.003
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发表时间：
2017-02-02
期刊：
影响因子：
23.9
通讯作者：
Bernstein BE
中科院分区：
文献类型：
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作者：
Liau BB;Sievers C;Donohue LK;Gillespie SM;Flavahan WA;Miller TE;Venteicher AS;Hebert CH;Carey CD;Rodig SJ;Shareef SJ;Najm FJ;van Galen P;Wakimoto H;Cahill DP;Rich JN;Aster JC;Suvà ML;Patel AP;Bernstein BE
胶质母细胞瘤是最常见和侵袭性的恶性脑肿瘤，是由干细胞样癌细胞传播的，对现有治疗方法无效。了解控制胶质母细胞瘤干细胞（GSC）增殖和耐药性的分子机制可能为治疗干预提供机会。在这里，我们表明GSCs可以可逆地转变为慢循环，持续状态，以响应靶向激酶抑制剂。在这种状态下，GSCs上调原始发育程序并依赖于Notch信号。这种转变伴随着抑制性组蛋白甲基化的广泛重新分布。因此，持久性GSCs上调并依赖于组蛋白去甲基化酶KDM6A/B。重要的是，治疗前原发性胶质母细胞瘤中存在高Notch活性和组蛋白去甲基化酶表达的慢循环细胞，这可能导致复发。我们的发现说明了癌细胞如何劫持原生发育程序的各个方面，以实现疯狂的增殖、适应和耐受性。他们还提出了通过靶向表观遗传和发育途径消除难治性肿瘤细胞的策略。
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.