Harnessing the link between BRAFV600E and metabolism in colorectal cancer

CRC is the third most common cancer worldwide and is responsible for 8% of all cancer deaths. 60-80% of CRCs arise through a well-understood adenoma-carcinoma sequence characterised by APC mutations and upregulated Wnt signalling, whereas 15-30% arise through an alternative, less characterized “serrated” pathway often harbouring BRAF^V600E mutations, with distinct clinical and morphological features and worse prognosis. Treatment options are limited, necessitating development of new therapeutic and preventative strategies.

Genetically engineered mouse models have been developed to study BRAF^V600E-mutant CRCs. However, in this context Braf^V600E proved to be a poor oncogene, with few lesions developing after long latency. Most studies analysed the short-term impact of Braf^V600E activation; instead, our objectives were to examine histological and transcriptomic features of intestinal tissue expressing Braf^V600E for up to 6 months, for comparison with short-term Braf^V600E induction (3 days) and with human data. We hypothesised that this approach could identify previously uncharacterised changes to be exploited in prevention and/or therapy.

We show that long-term Braf^V600E expression triggers hyperplasia and decreases gut barrier integrity. The number, distribution, and transcriptional signatures of differentiated epithelial cells were also affected without major changes to intestinal stem cells. Transcriptional analysis showed Braf^V600E increased proliferation and Wnt signalling signatures, whereas inflammatory signatures were downregulated. Cholesterol homeostasis increased after Braf^V600E expression, which was also reflected in human serrated adenomas. However, inflammatory pathways showed an opposite trend and were upregulated in adenomas. This suggests lack of inflammation limits tumour development in mutant mice, and that metabolic reprogramming sustains BRAF^V600E CRCs. Indeed, in vivo inhibition of cholesterol synthesis using statins reduced crypt hyperplasia, suggesting cholesterol metabolism could be targeted to prevent serrated neoplasia.

Overall, these results provide novel insights into the effects of Braf^V600E expression on the intestinal epithelium, unmasking transcriptional reprogramming and highlighting pathways to be exploited for preventative or therapeutic interventions.