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Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial c...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381612/ https://www.ncbi.nlm.nih.gov/pubmed/32709883 http://dx.doi.org/10.1038/s41467-020-17549-y |
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author | Aubert, Léo Nandagopal, Neethi Steinhart, Zachary Lavoie, Geneviève Nourreddine, Sami Berman, Jacob Saba-El-Leil, Marc K. Papadopoli, David Lin, Sichun Hart, Traver Macleod, Graham Topisirovic, Ivan Gaboury, Louis Fahrni, Christoph J. Schramek, Daniel Meloche, Sylvain Angers, Stephane Roux, Philippe P. |
author_facet | Aubert, Léo Nandagopal, Neethi Steinhart, Zachary Lavoie, Geneviève Nourreddine, Sami Berman, Jacob Saba-El-Leil, Marc K. Papadopoli, David Lin, Sichun Hart, Traver Macleod, Graham Topisirovic, Ivan Gaboury, Louis Fahrni, Christoph J. Schramek, Daniel Meloche, Sylvain Angers, Stephane Roux, Philippe P. |
author_sort | Aubert, Léo |
collection | PubMed |
description | Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms. |
format | Online Article Text |
id | pubmed-7381612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73816122020-07-28 Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer Aubert, Léo Nandagopal, Neethi Steinhart, Zachary Lavoie, Geneviève Nourreddine, Sami Berman, Jacob Saba-El-Leil, Marc K. Papadopoli, David Lin, Sichun Hart, Traver Macleod, Graham Topisirovic, Ivan Gaboury, Louis Fahrni, Christoph J. Schramek, Daniel Meloche, Sylvain Angers, Stephane Roux, Philippe P. Nat Commun Article Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms. Nature Publishing Group UK 2020-07-24 /pmc/articles/PMC7381612/ /pubmed/32709883 http://dx.doi.org/10.1038/s41467-020-17549-y Text en © The Author(s) 2020 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 Aubert, Léo Nandagopal, Neethi Steinhart, Zachary Lavoie, Geneviève Nourreddine, Sami Berman, Jacob Saba-El-Leil, Marc K. Papadopoli, David Lin, Sichun Hart, Traver Macleod, Graham Topisirovic, Ivan Gaboury, Louis Fahrni, Christoph J. Schramek, Daniel Meloche, Sylvain Angers, Stephane Roux, Philippe P. Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title | Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title_full | Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title_fullStr | Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title_full_unstemmed | Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title_short | Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer |
title_sort | copper bioavailability is a kras-specific vulnerability in colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381612/ https://www.ncbi.nlm.nih.gov/pubmed/32709883 http://dx.doi.org/10.1038/s41467-020-17549-y |
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