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

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Item Type:Article
Title:Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells
Creators Name:Iftekhar, A. and Berger, H. and Bouznad, N. and Heuberger, J. and Boccellato, F. and Dobrindt, U. and Hermeking, H. and Sigal, M. and Meyer, T.F.
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 in human CRC, suggesting a causal link. Here, we investigate its transformation potential using organoids from primary murine colon epithelial cells. Organoids recovered from short-term infection with pks+ E. coli show characteristics of CRC cells, e.g., enhanced proliferation, Wnt-independence, and impaired differentiation. Sequence analysis of Wnt-independent organoids reveals an enhanced mutational burden, including chromosomal aberrations typical of genomic instability. Although we do not find classic Wnt-signaling mutations, we identify several mutations in genes related to p53-signaling, including miR-34a. Knockout of Trp53 or miR-34 in organoids results in Wnt-independence, corroborating a functional interplay between the p53 and Wnt pathways. We propose larger chromosomal alterations and aneuploidy as the basis of transformation in these organoids, consistent with the early appearance of chromosomal instability in CRC.
Keywords:Chromosome Aberrations, Colon, Colonic Neoplasms, Colorectal Neoplasms, DNA Damage, Epithelial Cells, Escherichia coli, Genomics, Knockout Mice, Mutation, Organoids, Peptides, Polyketides, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:1003
Date:12 February 2021
Official Publication:https://doi.org/10.1038/s41467-021-21162-y
PubMed:View item in PubMed

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