Dataset Information

BRAF^V600E-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.

SUBMITTER: Rzasa P

PROVIDER: S-EPMC10514332 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Rzasa Paulina P Whelan Sarah S Farahmand Pooyeh P Cai Hong H Guterman Inna I Palacios-Gallego Raquel R Undru Shanthi S SS Sandford Lauren L Green Caleb C Andreadi Catherine C Mintseva Maria M Parrott Emma E Jin Hong H Hey Fiona F Giblett Susan S Sylvius Nicolas B NB Allcock Natalie S NS Straatman-Iwanowska Anna A Feuda Roberto R Tufarelli Cristina C Brown Karen K Pritchard Catrin C Rufini Alessandro A

Communications biology 20230921 1

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 BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, B ...[more]

PMID: 37735514

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Project description:BackgroundColorectal cancer (CRC) harboring BRAFV600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAFV600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies.MethodsBy injecting human CRC stem-like cells isolated from BRAFV600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities' functional profile was also predicted. Data were compared with Mann-Whitney U, Welch's t-test for unequal variances and Kruskal-Wallis test with Benjamini-Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed.ResultsA specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAFV600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAFV600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69-1.01).ConclusionOverall, our results suggest that BRAFV600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.

Dataset Information

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

Publications

BRAF<sup>V600E</sup>-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism.

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