BRAFV600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism
Paulina Rzasa, Sarah Whelan, Pooyeh Farahmand, Hong Cai, Inna Guterman, Raquel Palacios-Gallego, Shanthi Sri Undru, Lauren Sandford, Caleb Green, Catherine Andreadi, Maria Yu. Mintseva, Emma Parrott, Hong Ri Jin, Fiona Hey, Susan Giblett, Nicolas Sylvius, Natalie Allcock, Anna Straatman-Iwanowska, Roberto Feuda, Cristina Tufarelli, Karen Brown, Catrin Pritchard, Alessandro Rufini
Abstract
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 V600 E 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.