Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling

被引：137

作者：

Gimple, Ryan C. ^{[1
,2
]}

Kidwell, Reilly L. ^{[1
]}

Kim, Leo J. Y. ^{[1
,2
]}

Sun, Tengqian ^{[3
]}

Gromovsky, Anthony D. ^{[4
]}

Wu, Qiulian ^{[1
]}

Wolf, Megan ^{[5
]}

Lv, Deguan ^{[1
]}

Bhargava, Shruti ^{[1
]}

Jiang, Li ^{[1
]}

Prager, Briana C. ^{[1
,2
,6
]}

Wang, Xiuxing ^{[1
]}

Ye, Qing ^{[3
]}

Zhu, Zhe ^{[1
]}

Zhang, Guoxin ^{[1
]}

Dong, Zhen ^{[1
]}

Zhao, Linjie ^{[1
]}

Lee, Derrick ^{[1
]}

Bi, Junfeng ^{[7
]}

Sloan, Andrew E. ^{[8
,9
]}

Mischel, Paul S. ^{[7
,10
,11
]}

Brown, J. Mark ^{[4
]}

Cang, Hu ^{[3
]}

Huan, Tao ^{[5
]}

Mack, Stephen C. ^{[12
,13
]}

Xie, Qi ^{[1
,14
]}

Rich, Jeremy N. ^{[1
,11
,15
]}

机构：

[1] Univ Calif San Diego, Dept Med, Div Regenerat Med, San Diego, CA 92103 USA

[2] Case Western Univ, Dept Pathol, Cleveland, OH USA

[3] Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA

[5] Univ British Columbia, Dept Chem, Vancouver, BC, Canada

[6] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA

[7] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[8] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA

[9] Univ Hosp Cleveland, Med Ctr, Dept Neurol Surg, Cleveland, OH 44106 USA

[10] UCSD Sch Med, Dept Pathol, La Jolla, CA USA

[11] UCSD Sch Med, Moores Canc Ctr, La Jolla, CA USA

[12] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[13] Dan L Duncan Canc Ctr, Houston, TX USA

[14] Westlake Univ, Inst Basic Med Sci, Westlake Inst Adv Study, Hangzhou, Zhejiang, Peoples R China

[15] UCSD Sch Med, Dept Neurosci, La Jolla, CA USA

来源：

CANCER DISCOVERY | 2019年 / 9卷 / 09期

关键词：

IN-VITRO; HUMAN GLIOBLASTOMA; SUPER-ENHANCERS; CANCER; GROWTH; ACTIVATION; IDENTITY; MUTATION; DEPENDENCIES; INHIBITION;

D O I：

10.1158/2159-8290.CD-19-0061

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1248 / 1267

页数：20

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