Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Maude Jans, Magdalena Kolata, Gillian Blancke, Aline D’Hondt, Claudia Gräf, Maarten Ciers, Mozes Sze, Alexandra Thiran, Ioanna Petta, Vanessa Andries, Sara Verbandt, Engy Shokry, David Sumpton, Johan Vande Voorde, Geert Berx, Sabine Tejpar, Geert van Loo, Iliyan D. Iliev, Han Remaut and Lars Vereecke ()
Additional contact information
Maude Jans: VIB Center for Inflammation Research
Magdalena Kolata: Vrije Universiteit Brussel
Gillian Blancke: VIB Center for Inflammation Research
Aline D’Hondt: VIB-VUB Centre for Structural Biology
Claudia Gräf: VIB-VUB Centre for Structural Biology
Maarten Ciers: VIB Center for Inflammation Research
Mozes Sze: VIB Center for Inflammation Research
Alexandra Thiran: VIB Center for Inflammation Research
Ioanna Petta: VIB Center for Inflammation Research
Vanessa Andries: VIB Center for Inflammation Research
Sara Verbandt: Catholic University Leuven
Engy Shokry: Cancer Research UK Scotland Institute
David Sumpton: Cancer Research UK Scotland Institute
Johan Vande Voorde: University of Glasgow
Geert Berx: Ghent University
Sabine Tejpar: Catholic University Leuven
Geert van Loo: VIB Center for Inflammation Research
Iliyan D. Iliev: Cornell University
Han Remaut: Vrije Universiteit Brussel
Lars Vereecke: VIB Center for Inflammation Research

Nature, 2024, vol. 635, issue 8038, 472-480

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08135-z

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