2. Academic Validation
  3. Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

  • Nature. 2024 Nov;635(8038):472-480. doi: 10.1038/s41586-024-08135-z.
Maude Jans # 1 2 3,  Magdalena Kolata # 4 5,  Gillian Blancke 1 3 6,  Aline D'Hondt 5 6,  Claudia Gräf 5 6,  Maarten Ciers 1 2 3 6,  Mozes Sze 1 2,  Alexandra Thiran 1 3 6,  Ioanna Petta 1 3 6,  Vanessa Andries 1 6,  Sara Verbandt 7,  Engy Shokry 8,  David Sumpton 8 9,  Johan Vande Voorde 9,  Geert Berx 2 3,  Sabine Tejpar 7,  Geert van Loo 1 2 3,  Iliyan D Iliev 10 11,  Han Remaut 4 5,  Lars Vereecke 12 13 14
Affiliations

Affiliations

  • 1 VIB Center for Inflammation Research, Ghent, Belgium.
  • 2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 3 Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
  • 4 Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
  • 5 Structural & Molecular Microbiology, VIB-VUB Centre for Structural Biology, Brussels, Belgium.
  • 6 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
  • 7 Department of Oncology, Catholic University Leuven, Leuven, Belgium.
  • 8 Cancer Research UK Scotland Institute, Glasgow, UK.
  • 9 School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK.
  • 10 Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 11 The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA.
  • 12 VIB Center for Inflammation Research, Ghent, Belgium. lars.vereecke@irc.vib-ugent.be.
  • 13 Cancer Research Institute Ghent (CRIG), Ghent, Belgium. lars.vereecke@irc.vib-ugent.be.
  • 14 Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. lars.vereecke@irc.vib-ugent.be.
  • # Contributed equally.
PMID: 39506107 DOI: 10.1038/s41586-024-08135-z
Abstract

Various bacteria are suggested to contribute to colorectal Cancer (CRC) development1-5, including pks+ Escherichia coli, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells6. However, it remains unclear how the highly unstable colibactin molecule is able to access host epithelial cells to cause harm. Here, using the microbiota-dependent ZEB2-transgenic mouse model of invasive CRC7, we demonstrate that the oncogenic potential of pks+ E. coli critically depends on Bacterial adhesion to host epithelial cells, mediated by the type 1 pilus adhesin FimH and the F9 pilus adhesin FmlH. Blocking Bacterial adhesion using a pharmacological FimH inhibitor attenuates colibactin-mediated genotoxicity and CRC exacerbation. We also show that allelic switching of FimH strongly influences the genotoxic potential of pks+ E. coli and can induce a genotoxic gain-of-function in the probiotic strain Nissle 1917. Adhesin-mediated epithelial binding subsequently allows the production of the genotoxin colibactin in close proximity to host epithelial cells, which promotes DNA damage and drives CRC development. These findings present promising therapeutic routes for the development of anti-adhesive therapies aimed at mitigating colibactin-induced DNA damage and inhibiting the initiation and progression of CRC, particularly in individuals at risk for developing CRC.

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