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

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. Colibactin-producing pks+Escherichia coli are frequent constituents of the human intestinal microbiota. Here, the authors show that short exposure of cells to pks+E. coli induces chromosomal aberrations, genomic instability, and multiple features of transformation reminiscent of colorectal cancer.

• Publication year

  2021

• Venue

  Nature Communications

• Publication date

  2021-02-12

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41467-021-21162-yPMID 33579932PMCID 7881031
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2023cites this paper
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