Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Léo Aubert; Neethi Nandagopal; Zachary Steinhart; Geneviève Lavoie; Sami Nourreddine; Jacob Berman; Marc K. Saba-El-Leil; David Papadopoli; Sichun Lin; Traver Hart; Graham Macleod; Ivan Topisirovic; Louis Gaboury; Christoph J. Fahrni; Daniel Schramek; Sylvain Meloche; Stephane Angers; Philippe P. Roux

doi:10.1038/s41467-020-17549-y

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Léo Aubert, Neethi Nandagopal, Zachary Steinhart, Geneviève Lavoie, Sami Nourreddine, Jacob Berman, Marc K. Saba-El-Leil, David Papadopoli, Sichun Lin, Traver Hart, Graham Macleod, Ivan Topisirovic, Louis Gaboury, Christoph J. Fahrni, Daniel Schramek, Sylvain Meloche, Stephane Angers, Philippe P. Roux

Bioinformatics & Computational Biology

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

Abstract

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.

Original language	English (US)
Article number	3701
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17549-y
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Aubert, L., Nandagopal, N., Steinhart, Z., Lavoie, G., Nourreddine, S., Berman, J., Saba-El-Leil, M. K., Papadopoli, D., Lin, S., Hart, T., Macleod, G., Topisirovic, I., Gaboury, L., Fahrni, C. J., Schramek, D., Meloche, S., Angers, S., & Roux, P. P. (2020). Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer. Nature communications, 11(1), Article 3701. https://doi.org/10.1038/s41467-020-17549-y

Aubert, L, Nandagopal, N, Steinhart, Z, Lavoie, G, Nourreddine, S, Berman, J, Saba-El-Leil, MK, Papadopoli, D, Lin, S, Hart, T, Macleod, G, Topisirovic, I, Gaboury, L, Fahrni, CJ, Schramek, D, Meloche, S, Angers, S & Roux, PP 2020, 'Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer', Nature communications, vol. 11, no. 1, 3701. https://doi.org/10.1038/s41467-020-17549-y

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abstract = "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.",

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AU - Berman, Jacob

AU - Saba-El-Leil, Marc K.

AU - Papadopoli, David

AU - Lin, Sichun

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AU - Macleod, Graham

AU - Topisirovic, Ivan

AU - Gaboury, Louis

AU - Fahrni, Christoph J.

AU - Schramek, Daniel

AU - Meloche, Sylvain

AU - Angers, Stephane

AU - Roux, Philippe P.

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N2 - 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.

AB - 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.

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Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer

Abstract

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