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Title:
A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis | Nature Communications
Description:
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. Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
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Keywords {🔍}
cells, cell, ferroptosis, cancer, article, fig, scholar, supplementary, google, data, cas, sensitivity, gpx, lipid, analysis, hifα, cccs, hilpda, nature, experiments, expression, carcinoma, genes, lines, ccrcc, protein, susceptibility, viability, levels, epas, renal, clearcell, rsl, treated, gene, crispr, screening, clear, death, pathway, results, ccc, representative, media, including, metabolic, treatment, sgrna, condition, state,
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crispr/cas9-mediated genome editing crispr/cas9-mediated genome-editing /remontoire-pac/ctrp-reference/tree/master/auc] nature portfolio gov/programs/ctd2/data-portal] gov/pub/ocg-dcc/ctd2/broad/] privacy policy iron-dependent cell-death pathway15 irdye 800cw goat-anti-rabbit hif-2α/hif-1β protein levels advertising epas1-targeting sgrna-expressing 786-o-cas9 index sequence identification p62-keap1-nrf2 pathway protects sensitized hif-2α-null cells 2 × 150 bp paired-end configuration hif-2α/gpx4 double knockouts reporting summary barely impacted sfa/mufa-lipids hif-2α-regulated molecular program previous chip-seq data tailed mann–whitney–wilcoxon test kidney cancer research papillary renal-cell carcinoma lipidomics data analysis identified hif-2α-dependent genes hif-2α-dependent genes identified high-score g0s2-targeting sgrna reprints dynamic nature von hippel-lindau protein homologous pnpla-binding motif saturated/monounsaturated fatty acyl metastatic renal-cell carcinoma vinyl ether-linked pe-plasmalogens von hippel-lindau gene personal research funds pufa-lipid-enriched cell state genome-wide crispr screen lc-ms system comprising mann–whitney–wilcoxon tests ovarian clear-cell carcinoma supplementary data tables hif-1/2α mediates sensitivity rna-seq data analysis hif-2α/hif-1β sequence-independent g0s2-targeting shrnas hif-2α-depletion induced gpx4-dependent cell state author information authors
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headline:A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
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datePublished:2019-04-08T00:00:00Z
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Cancer metabolism
Cell death
Lipidomics
Ovarian cancer
Renal cell carcinoma
Science
Humanities and Social Sciences
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headline:A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
description: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. Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
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affiliation:
name:The Broad Institute
address:
name:The Broad Institute, Cambridge, USA
type:PostalAddress
type:Organization
name:Paul A. Clemons
url:http://orcid.org/0000-0002-1800-5112
affiliation:
name:The Broad Institute
address:
name:The Broad Institute, Cambridge, USA
type:PostalAddress
type:Organization
name:Stuart L. Schreiber
url:http://orcid.org/0000-0003-1922-7558
affiliation:
name:The Broad Institute
address:
name:The Broad Institute, Cambridge, USA
type:PostalAddress
type:Organization
name:Harvard University
address:
name:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:The Broad Institute, Cambridge, USA
name:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:Department of Oncologic Pathology, Dana-Farber Cancer Institute and Brigham and Womenâs Hospital, Harvard Medical School, Boston, USA
name:Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Womenâs Hospital, Harvard Medical School, Boston, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:The Broad Institute, Cambridge, USA
name:Department of Chemistry and Chemical Biology, Harvard University, Cambridge, USA
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