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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-04-08

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

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. More... »

PAGES

1617

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-019-09277-9

    DOI

    http://dx.doi.org/10.1038/s41467-019-09277-9

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1113300643

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30962421


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