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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39506107/
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. 2024 Nov;635(8038):472-480.
doi: 10.1038/s41586-024-08135-z. Epub 2024 Nov 6.

Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

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
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Colibactin-driven colon cancer requires adhesin-mediated epithelial binding

Maude Jans et al. Nature. 2024 Nov.

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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Conflict of interest statement

Competing interests The authors declare no competing interests.

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