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

Author

Listed:
  • Amina Iftekhar

    (Max Planck Institute for Infection Biology)

  • Hilmar Berger

    (Max Planck Institute for Infection Biology
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel and University Hospital Schleswig Holstein – Campus Kiel
    Charité University Medicine)

  • Nassim Bouznad

    (Institute of Pathology, Ludwig Maximilians University)

  • Julian Heuberger

    (Max Planck Institute for Infection Biology
    Charité University Medicine)

  • Francesco Boccellato

    (Max Planck Institute for Infection Biology
    Ludwig Institute for Cancer Research, University of Oxford)

  • Ulrich Dobrindt

    (Institute of Hygiene, University of Münster)

  • Heiko Hermeking

    (Institute of Pathology, Ludwig Maximilians University
    German Cancer Consortium (DKTK), Partner Site München
    German Cancer Research Center (DKFZ))

  • Michael Sigal

    (Max Planck Institute for Infection Biology
    Charité University Medicine
    Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine)

  • Thomas F. Meyer

    (Max Planck Institute for Infection Biology
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel and University Hospital Schleswig Holstein – Campus Kiel)

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.

Suggested Citation

  • Amina Iftekhar & Hilmar Berger & Nassim Bouznad & Julian Heuberger & Francesco Boccellato & Ulrich Dobrindt & Heiko Hermeking & Michael Sigal & Thomas F. Meyer, 2021. "Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21162-y
    DOI: 10.1038/s41467-021-21162-y
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    Cited by:

    1. Bingjie Guan & Youdong Liu & Bowen Xie & Senlin Zhao & Abudushalamu Yalikun & Weiwei Chen & Menghua Zhou & Qi Gu & Dongwang Yan, 2024. "Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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