RRC ID 59702
Author Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng YY, Deasy R, Kost-Alimova M, Dančík V, Leshchiner ES, Viswanathan VS, Signoretti S, Choueiri TK, Boehm JS, Wagner BK, Doench JG, Clish CB, Clemons PA, Schreiber SL.
Title A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.
Journal Nat Commun
Abstract 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-2α 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.
Volume 10(1)
Pages 1617
Published 2019-4-8
DOI 10.1038/s41467-019-09277-9
PII 10.1038/s41467-019-09277-9
PMID 30962421
PMC PMC6453886
MeSH Aged Animals Apoptosis / genetics Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* CRISPR-Cas Systems / genetics Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / pathology* Cell Line, Tumor Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockout Techniques Glutathione Peroxidase / genetics Glutathione Peroxidase / metabolism* HEK293 Cells Humans Iron / metabolism Kidney Neoplasms / genetics Kidney Neoplasms / pathology* Lipid Peroxidation / genetics Male Mice, Nude Middle Aged Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Phospholipid Hydroperoxide Glutathione Peroxidase RNA Interference Xenograft Model Antitumor Assays
IF 11.878
Times Cited 33
Human and Animal Cells RCC10RGB(RCB1151)