Cytolethal distending toxin modulates cell differentiation and elicits epithelial to mesenchymal transition

Lamia Azzi-Martin; Valentin Touffait-Calvez; Maude Everaert; Ruxue Jia; Elodie Sifré; Lornella Seeneevassen; Christine Varon; Pierre Dubus; Armelle Ménard

doi:10.1093/infdis/jiae105

Cytolethal distending toxin modulates cell differentiation and elicits epithelial to mesenchymal transition

J Infect Dis. 2024 Feb 28:jiae105. doi: 10.1093/infdis/jiae105. Online ahead of print.

Authors

Lamia Azzi-Martin^{1

2}, Valentin Touffait-Calvez¹, Maude Everaert¹, Ruxue Jia¹, Elodie Sifré¹, Lornella Seeneevassen¹, Christine Varon^{1

2}, Pierre Dubus^{1

2

3}, Armelle Ménard¹

Affiliations

¹ BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, Univ. Bordeaux, F-33000, Bordeaux, France.
² Univ. Bordeaux, UFR des Sciences Médicales, 33076 Bordeaux, France.
³ CHU de Bordeaux, Institut de Pathologie et de Biologie du Cancer, Bordeaux, France.

PMID: 38416880
DOI: 10.1093/infdis/jiae105

Abstract

Background: The bacterial genotoxin, cytolethal distending toxin (CDT), causes DNA damage in host cells, a risk factor for carcinogenesis. Previous studies have shown that CDT induces phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process involved in cancer initiation and progression.

Methods: We investigated different steps of EMT in response to Helicobacter hepaticus CDT and its active CdtB subunit using in vivo and in vitro models.

Results: Most of the steps of the EMT process were induced by CDT/CdtB and observed throughout the study in murine and epithelial cell culture models. CdtB induced cell-cell junctions' disassembly, causing individualization of cells and acquisition of a spindle-like morphology. The key transcriptional regulators of EMT (SNAIL1 and ZEB1) and some EMT markers were upregulated at both RNA and protein levels in response to CDT/CdtB. CdtB increased the expression and proteolytic activity of matrix metalloproteinases, as well as cell migration. A range of these results were confirmed in Helicobacter hepaticus infected and xenograft murine models. In addition, colibactin, a genotoxic metabolite produced by Escherichia coli, induced EMT-like effects in cell culture.

Conclusion: Overall, these data show that infection with genotoxin-producing bacteria elicits EMT process activation, supporting their role in tumorigenesis.

Keywords: Helicobacter hepaticus; Fibronectin; MMP2; MMP9; SNAIL; Vimentin; ZEB1; cell-cell junctions; colibactin; cytolethal distending toxin; epithelial to mesenchymal transition; genotoxin; integrin; matrix metalloproteinases; migration.