BRAFV600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism

Abstract

BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf^V600E in the intestinal tissue of an inducible mouse model. We show that Braf^V600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, Braf^V600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in Braf^V600E-mutant mice. Overall, our work unveils the long-term impact of Braf^V600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.

Short- and long-term expression of Braf^V600E in the intestinal epithelium of mice perturbs the homeostasis of intestinal epithelial cells and leads to transcriptional reprogramming that favors tumorigenesis and metabolic rewiring.