BRAF V600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism

Paulina Rzasa, Sarah Whelan, Pooyeh Farahmand, Hong Cai, Inna Guterman, Raquel Palacios-Gallego, Shanthi S. Undru, Lauren Sandford, Caleb Green, Catherine Andreadi, Maria Mintseva, Emma Parrott, Hong Jin, Fiona Hey, Susan Giblett, Nicolas B. Sylvius, Natalie S. Allcock, Anna Straatman-Iwanowska, Roberto Feuda, Cristina TufarelliKaren Brown, Catrin Pritchard, Alessandro Rufini

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Article number962
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023
Externally publishedYes

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