Colibactin causes genomic instability and promotes Wnt independence in primary colon epithelial cells. Colibactin causes genomic instability and promotes Wnt independence in primary colon epithelial cells

Colorectal cancer is driven by a sequential cascade of mutations known as the adenoma-carcinoma sequence. Recent studies have revealed that specific bacterial species present in the colonic microbiota can induce mutations and contribute to this malignancy. Specifically, genotoxic colibactin-producing pks+ Escherichia coli strains can induce DNA double strand breaks (DSBs) and promote tumor development in mouse models of colorectal cancer. Here, we investigated the transformation potential of colibactin by using organoids and polarized monolayers derived from primary murine colon epithelial cells and reveal striking phenotypic changes upon short-term infection. This study demonstrates the direct pro-oncogenic potential of pks+ E. coli, as such transformations in vivo could facilitate colitis-associated colorectal carcinogenesis. Overall design: RNAseq of mouse colorectal epithelium (Wnt independent organoids derived from pks+ infected cells and uninfected control organids)

结直肠癌（colorectal cancer）由被称为腺瘤-腺癌序列（adenoma-carcinoma sequence）的连续突变级联反应所驱动。近期研究表明，结肠菌群（colonic microbiota）中存在的特定细菌菌种可诱发突变并推动该恶性肿瘤的发生发展。具体而言，产基因毒性colibactin的pks+大肠埃希菌（Escherichia coli）菌株可诱发DNA双链断裂（DNA double strand breaks, DSBs），并在结直肠癌小鼠模型中促进肿瘤发生。本研究利用原代小鼠结肠上皮细胞来源的类器官（organoids）与极化单层细胞，探究了colibactin的转化潜能，并发现短期感染后会出现显著的表型变化。本研究证实了pks+大肠埃希菌具有直接的促癌潜能，此类体内转化事件可促进结肠炎相关结直肠癌的发生。实验设计方案：小鼠结直肠上皮细胞的RNA测序（RNAseq），样本包括pks+感染细胞来源的Wnt非依赖型类器官以及未感染的对照类器官。