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Colibactin-driven colon cancer requires adhesin-mediated epithelial binding
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Journal Article
Colibactin-driven colon cancer requires adhesin-mediated epithelial binding
2024
Overview
Various bacteria are suggested to contribute to colorectal cancer (CRC) development
1
–
5
, including
pks
+
Escherichia coli
, which produces the genotoxin colibactin that induces characteristic mutational signatures in host epithelial cells
6
. 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 CRC
7
, 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.
The oncogenic potential of
pks
+
Escherichia coli
depends critically on bacterial adhesion to host epithelial cells mediated by the type 1 pilus adhesin FimH and the F9 pilus adhesin FmlH.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 13/44
/ 13/51
/ 14/19
/ 14/63
/ 64/60
/ 82/80
/ Adhesins, Escherichia coli - genetics
/ Adhesins, Escherichia coli - metabolism
/ Adhesion
/ Animals
/ Binding
/ Colorectal Neoplasms - chemically induced
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - microbiology
/ Colorectal Neoplasms - pathology
/ Damage
/ DNA
/ E coli
/ Epithelial Cells - drug effects
/ Epithelial Cells - metabolism
/ Epithelial Cells - microbiology
/ Epithelial Cells - pathology
/ Escherichia coli - classification
/ Escherichia coli - metabolism
/ Escherichia coli - pathogenicity
/ Female
/ Fimbriae Proteins - genetics
/ Fimbriae Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mice
/ Pili
/ Science
