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A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
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 vulnera...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453886/ https://www.ncbi.nlm.nih.gov/pubmed/30962421 http://dx.doi.org/10.1038/s41467-019-09277-9 |
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author | Zou, Yilong Palte, Michael J. Deik, Amy A. Li, Haoxin Eaton, John K. Wang, Wenyu Tseng, Yuen-Yi Deasy, Rebecca Kost-Alimova, Maria Dančík, Vlado Leshchiner, Elizaveta S. Viswanathan, Vasanthi S. Signoretti, Sabina Choueiri, Toni K. Boehm, Jesse S. Wagner, Bridget K. Doench, John G. Clish, Clary B. Clemons, Paul A. Schreiber, Stuart L. |
author_facet | Zou, Yilong Palte, Michael J. Deik, Amy A. Li, Haoxin Eaton, John K. Wang, Wenyu Tseng, Yuen-Yi Deasy, Rebecca Kost-Alimova, Maria Dančík, Vlado Leshchiner, Elizaveta S. Viswanathan, Vasanthi S. Signoretti, Sabina Choueiri, Toni K. Boehm, Jesse S. Wagner, Bridget K. Doench, John G. Clish, Clary B. Clemons, Paul A. Schreiber, Stuart L. |
author_sort | Zou, Yilong |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-6453886 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64538862019-04-10 A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis Zou, Yilong Palte, Michael J. Deik, Amy A. Li, Haoxin Eaton, John K. Wang, Wenyu Tseng, Yuen-Yi Deasy, Rebecca Kost-Alimova, Maria Dančík, Vlado Leshchiner, Elizaveta S. Viswanathan, Vasanthi S. Signoretti, Sabina Choueiri, Toni K. Boehm, Jesse S. Wagner, Bridget K. Doench, John G. Clish, Clary B. Clemons, Paul A. Schreiber, Stuart L. Nat Commun Article 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. Nature Publishing Group UK 2019-04-08 /pmc/articles/PMC6453886/ /pubmed/30962421 http://dx.doi.org/10.1038/s41467-019-09277-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zou, Yilong Palte, Michael J. Deik, Amy A. Li, Haoxin Eaton, John K. Wang, Wenyu Tseng, Yuen-Yi Deasy, Rebecca Kost-Alimova, Maria Dančík, Vlado Leshchiner, Elizaveta S. Viswanathan, Vasanthi S. Signoretti, Sabina Choueiri, Toni K. Boehm, Jesse S. Wagner, Bridget K. Doench, John G. Clish, Clary B. Clemons, Paul A. Schreiber, Stuart L. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title | A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title_full | A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title_fullStr | A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title_full_unstemmed | A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title_short | A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
title_sort | gpx4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453886/ https://www.ncbi.nlm.nih.gov/pubmed/30962421 http://dx.doi.org/10.1038/s41467-019-09277-9 |
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