A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis

被引：898

作者：

Zou, Yilong ^{[1
,2
]}

Palte, Michael J. ^{[1
]}

Deik, Amy A. ^{[1
]}

Li, Haoxin ^{[1
,2
]}

Eaton, John K. ^{[1
]}

Wang, Wenyu ^{[1
]}

Tseng, Yuen-Yi ^{[1
]}

Deasy, Rebecca ^{[1
]}

Kost-Alimova, Maria ^{[1
]}

Dancik, Vlado ^{[1
]}

Leshchiner, Elizaveta S. ^{[1
]}

Viswanathan, Vasanthi S. ^{[1
]}

Signoretti, Sabina ^{[3
,4
]}

Choueiri, Toni K. ^{[4
,5
]}

Boehm, Jesse S. ^{[1
]}

Wagner, Bridget K. ^{[1
]}

Doench, John G. ^{[1
]}

Clish, Clary B. ^{[1
]}

Clemons, Paul A. ^{[1
]}

Schreiber, Stuart L. ^{[1
,2
]}

机构：

[1] Broad Inst, Cambridge, MA 02142 USA

[2] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[3] Harvard Med Sch, Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02215 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA

[5] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

HIPPEL-LINDAU GENE; OVARIAN-CANCER; FATTY-ACIDS; CARCINOMA; EXPRESSION; DEATH; DRUG; TARGET; HOMEOSTASIS; DEPENDENCY;

D O I：

10.1038/s41467-019-09277-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2 alpha selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.

引用

页数：13

共 71 条

[1]

Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation [J].

Ackerman, Daniel ;

Tumanov, Sergey ;

Qiu, Bo ;

Michalopoulou, Evdokia ;

Spata, Michelle ;

Azzam, Andrew ;

Xie, Hong ;

Simon, M. Celeste ;

Kamphorst, Jurre J. .

CELL REPORTS, 2018, 24 (10) :2596-+

[2]

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice [J].

Angeli, Jose Pedro Friedmann ;

Schneider, Manuela ;

Proneth, Bettina ;

Tyurina, Yulia Y. ;

Tyurin, Vladimir A. ;

Hammond, Victoria J. ;

Herbach, Nadja ;

Aichler, Michaela ;

Walch, Axel ;

Eggenhofer, Elke ;

Basavarajappa, Devaraj ;

Radmark, Olof ;

Kobayashi, Sho ;

Seibt, Tobias ;

Beck, Heike ;

Neff, Frauke ;

Esposito, Irene ;

Wanke, Ruediger ;

Foerster, Heidi ;

Yefremova, Olena ;

Heinrichmeyer, Marc ;

Bornkamm, Georg W. ;

Geissler, Edward K. ;

Thomas, Stephen B. ;

Stockwell, Brent R. ;

O'Donnell, Valerie B. ;

Kagan, Valerian E. ;

Schick, Joel A. ;

Conrad, Marcus .

NATURE CELL BIOLOGY, 2014, 16 (12) :1180-U120

[3]

Clear cell hepatocellular carcinoma: origin, metabolic traits and fate of glycogenotic clear and ground glass cells [J].

Bannasch, Peter ;

Ribback, Silvia ;

Su, Qin ;

Mayer, Doris .

HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, 2017, 16 (06) :570-594

[4]

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[5]

An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules [J].

Basu, Amrita ;

Bodycombe, Nicole E. ;

Cheah, Jaime H. ;

Price, Edmund V. ;

Liu, Ke ;

Schaefer, Giannina I. ;

Ebright, Richard Y. ;

Stewart, Michelle L. ;

Ito, Daisuke ;

Wang, Stephanie ;

Bracha, Abigail L. ;

Liefeld, Ted ;

Wawer, Mathias ;

Gilbert, Joshua C. ;

Wilson, Andrew J. ;

Stransky, Nicolas ;

Kryukov, Gregory V. ;

Dancik, Vlado ;

Barretina, Jordi ;

Garraway, Levi A. ;

Hon, C. Suk-Yee ;

Munoz, Benito ;

Bittker, Joshua A. ;

Stockwell, Brent R. ;

Khabele, Dineo ;

Stern, Andrew M. ;

Clemons, Paul A. ;

Shamji, Alykhan F. ;

Schreiber, Stuart L. .

CELL, 2013, 154 (05) :1151-1161

[6]

BROWER M, 1986, CANCER RES, V46, P6012

[7]

Overexpression of PLIN2 is a prognostic marker and attenuates tumor progression in clear cell renal cell carcinoma [J].

Cao, Qi ;

Ruan, Hailong ;

Wang, Keshan ;

Song, Zhengshuai ;

Bao, Lin ;

Xu, Tianbo ;

Xiao, Haibing ;

Wang, Cheng ;

Cheng, Gong ;

Tong, Junwei ;

Meng, Xiangui ;

Liu, Di ;

Yang, Hongmei ;

Chen, Ke ;

Zhang, Xiaoping .

INTERNATIONAL JOURNAL OF ONCOLOGY, 2018, 53 (01) :137-147

[8]

Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration [J].

Carlson, Bradley A. ;

Tobe, Ryuta ;

Yefremova, Elena ;

Tsuji, Petra A. ;

Hoffmann, Victoria J. ;

Schweizer, Ulrich ;

Gladyshev, Vadim N. ;

Hatfield, Dolph L. ;

Conrad, Marcus .

REDOX BIOLOGY, 2016, 9 :22-31

[9]

Targeting renal cell carcinoma with a HIF-2 antagonist [J].

Chen, Wenfang ;

Hill, Haley ;

Christie, Alana ;

Kim, Min Soo ;

Holloman, Eboni ;

Pavia-Jimenez, Andrea ;

Homayoun, Farrah ;

Ma, Yuanqing ;

Patel, Nirav ;

Yell, Paul ;

Hao, Guiyang ;

Yousuf, Qurratulain ;

Joyce, Allison ;

Pedrosa, Ivan ;

Geiger, Heather ;

Zhang, He ;

Chang, Jenny ;

Gardner, Kevin H. ;

Bruick, Richard K. ;

Reeves, Catherine ;

Hwang, Tae Hyun ;

Courtney, Kevin ;

Frenkel, Eugene ;

Sun, Xiankai ;

Zojwalla, Naseem ;

Wong, Tai ;

Rizzi, James P. ;

Wallace, Eli M. ;

Josey, John A. ;

Xie, Yang ;

Xie, Xian-Jin ;

Kapur, Payal ;

McKay, Renee M. ;

Brugarolas, James .

NATURE, 2016, 539 (7627) :112-+

[10]

On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models [J].

Cho, Hyejin ;

Du, Xinlin ;

Rizzi, James P. ;

Liberzon, Ella ;

Chakraborty, Abhishek A. ;

Gao, Wenhua ;

Carvo, Ingrid ;

Signoretti, Sabina ;

Bruick, Richard K. ;

Josey, John A. ;

Wallace, Eli M. ;

Kaelin, William G., Jr. .

NATURE, 2016, 539 (7627) :107-+

← 1 2 3 4 5 6 7 8 →