BRAF^V600E 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.