BRAFV600E expression in intestinal tissue promotes a cholesterol metabolic gene signature that sustains hyperplasia and characterizes serrated colorectal neoplasia (RNA-Seq)

BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are 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, BrafV600E 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 BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins. Overall design: 9 samples

BRAF突变（BRAF）在锯齿状结直肠癌中早期即已发生，但其对组织稳态的长期影响尚待充分表征。本研究借助诱导型小鼠模型，探究了BrafV600E在肠道组织中短期（3天）与长期（6个月）表达的效应。研究结果显示，BrafV600E会扰乱肠道上皮细胞的稳态；在该癌基因长期表达后，肠细胞的分化缺陷逐渐显现。此外，BrafV600E可诱发持续性转录重编程，富集大量提示细胞增殖与肿瘤发生的基因特征，同时存在提示代谢重编程的特征富集。我们聚焦于排名最高的胆固醇生物合成基因特征，并证实其在人类锯齿状病变组织中表达显著上调。功能实验表明，降胆固醇药物阿托伐他汀可抑制BrafV600E突变小鼠肠道隐窝增生的形成。综上，本研究揭示了BrafV600E在肠道组织中表达的长期影响，并提示携带BRAF突变的结直肠癌或可通过他汀类药物实现预防。实验总体设计：共9个样本。