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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
         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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      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:Amy A. Deik
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Haoxin Li
      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
      name:John K. Eaton
      url:http://orcid.org/0000-0003-4633-5546
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Wenyu Wang
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Yuen-Yi Tseng
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Rebecca Deasy
      url:http://orcid.org/0000-0001-9143-6296
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Maria Kost-Alimova
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Vlado Dančík
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Elizaveta S. Leshchiner
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Vasanthi S. Viswanathan
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Sabina Signoretti
      affiliation:
            name:Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School
            address:
               name:Department of Oncologic Pathology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Toni K. Choueiri
      url:http://orcid.org/0000-0002-9201-3217
      affiliation:
            name:Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Jesse S. Boehm
      url:http://orcid.org/0000-0002-6795-6336
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Bridget K. Wagner
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:John G. Doench
      url:http://orcid.org/0000-0002-3707-9889
      affiliation:
            name:The Broad Institute
            address:
               name:The Broad Institute, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Clary B. Clish
      url:http://orcid.org/0000-0001-8259-9245
      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 Women’s Hospital, Harvard Medical School, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s 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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