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

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.

• Authors: Yilong Zou, Michael J Palte, Amy A Deik, Haoxin Li, John K Eaton, Wenyu Wang, Yuen-Yi Tseng, Rebecca Deasy, Maria Kost-Alimova, Vlado Dančík, Elizaveta S Leshchiner, Vasanthi S Viswanathan, Sabina Signoretti, Toni K Choueiri, Jesse S Boehm, Bridget K Wagner, John G Doench, Clary B Clish, Paul A Clemons, Stuart L Schreiber
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1617 (04 08 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30962421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• HILPDA protein, human
• Neoplasm Proteins
• endothelial PAS domain-containing protein 1
• Iron
• Phospholipid Hydroperoxide Glutathione Peroxidase
• Glutathione Peroxidase

Topics

• Aged
• Animals
• Apoptosis (genetics)
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• CRISPR-Cas Systems (genetics)
• Carcinoma, Renal Cell (genetics, pathology)
• Cell Line, Tumor
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Glutathione Peroxidase (genetics, metabolism)
• HEK293 Cells
• Humans
• Iron (metabolism)
• Kidney Neoplasms (genetics, pathology)
• Lipid Peroxidation (genetics)
• Male
• Mice, Nude
• Middle Aged
• Neoplasm Proteins (genetics, metabolism)
• Phospholipid Hydroperoxide Glutathione Peroxidase
• RNA Interference
• Xenograft Model Antitumor Assays