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

The presence of BRAF^V600E 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 BRAF^V600E, sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAF^V600E tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAF^V600E 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. BRAF^V600E 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 BRAF^V600E-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs. [Display omitted] • BRAF^V600E drives expression of glutamate-cysteine ligase (GCL) in colorectal cancer • GCLC-mediated glutathione synthesis increases resistance to oxidative stress • The BRAF^V600E-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 BRAF^V600E 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. [ABSTRACT FROM AUTHOR]