Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells

Abstract Genotoxic colibactin-producing pks + Escherichia coli induce DNA double-strand breaks, mutations, and promote tumor development in mouse models of colorectal cancer (CRC). Colibactin’s distinct mutational signature is reflected human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered short-term infection with E. show characteristics CRC cells, e.g., enhanced proliferation, Wnt-independence, impaired differentiation. Sequence analysis Wnt-independent reveals an burden, including chromosomal aberrations typical genomic instability. Although do not find classic Wnt-signaling identify several mutations genes related to p53-signaling, miR-34a . Knockout Trp53 or miR-34 results corroborating functional interplay between the p53 Wnt pathways. We propose larger alterations aneuploidy as basis these organoids, consistent early appearance instability CRC.