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

Amina Iftekhar, Hilmar Berger, Nassim Bouznad, Julian Heuberger, Francesco Boccellato, Ulrich Dobrindt, Heiko Hermeking, Michael Sigal () and Thomas F. Meyer ()
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Amina Iftekhar: Max Planck Institute for Infection Biology
Hilmar Berger: Max Planck Institute for Infection Biology
Nassim Bouznad: Institute of Pathology, Ludwig Maximilians University
Julian Heuberger: Max Planck Institute for Infection Biology
Francesco Boccellato: Max Planck Institute for Infection Biology
Ulrich Dobrindt: Institute of Hygiene, University of Münster
Heiko Hermeking: Institute of Pathology, Ludwig Maximilians University
Michael Sigal: Max Planck Institute for Infection Biology
Thomas F. Meyer: Max Planck Institute for Infection Biology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21162-y

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