Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling
Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling
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DOI：
10.1158/2159-8290.cd-19-0061
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发表时间：
2019-09-01
期刊：
影响因子：
28.2
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
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作者：
Gimple, Ryan C.;Kidwell, Reilly L.;Rich, Jeremy N.
胶质母细胞瘤是所有人类癌症中最具侵袭性和致命性的。功能定义的胶质瘤干细胞（GSC）通过驱动治疗抗性和维持细胞异质性而导致这种不良预后。为了了解GSC维持和致瘤性所必需的分子过程，我们询问了原发性胶质母细胞瘤标本和体外GSC的超增强景观。GSC表观遗传上上调了一种关键的多不饱和脂肪酸合成酶-GSHVL 2。靶向HPVL 2抑制胶质母细胞瘤细胞生长和肿瘤起始。CD 3VL 2耗竭改变了细胞膜磷脂组成。破坏膜结构特性。并通过控制脂肪酸延长减少EGFR信号传导。在支持这些研究结果的翻译潜力，多不饱和脂肪酸合成和EGFR信号的双重靶向GSCs.SIGNIFICANCE组合细胞毒性效应：胶质母细胞瘤仍然是一个毁灭性的疾病，尽管广泛的表征。我们分析了胶质母细胞瘤的表观基因组景观，以确定细胞状态特异性依赖性和治疗漏洞。GSC利用多不饱和脂肪酸合成来支持膜结构，其抑制损害EGFR信号传导和GSC增殖。这些网络的组合靶向代表了一种有前途的治疗策略。
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition. disrupted membrane structural properties. and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs.SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.