BRAFV600E in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis

• Published in: Cell reports (Cambridge) Vol. 41; no. 9; p. 111728
• Main Authors: Laoukili, Jamila, van Schelven, Susanne, Küçükköse, Emre, Verheem, André, Goey, Kaitlyn, Koopman, Miriam, Borel Rinkes, Inne, Kranenburg, Onno
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 29-11-2022
• Subjects: BRAFV600E; colorectal; glutathione; metastasis; metastatic organotropsim; oxidative stress; BRAFV600E; colorectal; metastasis; glutathione; CP: Cancer; metastatic organotropsim; oxidative stress
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111728

The presence of BRAFV600E in colorectal cancer (CRC) is associated with a higher chance of distant metastasis. Oxidative stress in disseminated tumor cells limits metastatic capacity. To study the relationship between BRAFV600E, sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAFV600E tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAFV600E PDOs strongly reduces their capacity to form distant liver and lung metastases but does not affect peritoneal metastasis outgrowth. Vice versa, the glutathione precursor N-acetyl-cysteine promotes organ-site-specific metastasis in the liver and the lungs but not in the peritoneum. BRAFV600E confers resistance to pharmacologically induced oxidative stress in vitro, which is partially overcome by treatment with the BRAF-inhibitor vemurafenib. We conclude that GCL-driven glutathione synthesis protects BRAFV600E-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs.
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•BRAFV600E drives expression of glutamate-cysteine ligase (GCL) in colorectal cancer•GCLC-mediated glutathione synthesis increases resistance to oxidative stress•The BRAFV600E-GCLC-glutathione pathway promotes liver and lung metastasis formation•The pathway does not control formation of primary tumors or peritoneal metastases
The mechanisms governing distant metastasis formation in colorectal cancer are incompletely understood. Laoukili et al. show that the BRAFV600E oncogene increases the capacity of disseminated tumor cells to withstand metastasis-associated oxidative stress by stimulating glutathione synthesis. This pathway promotes the formation of liver and lung metastases but not peritoneal metastases.