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The E. coli CNF1 toxin induces fetal reprogramming of intestinal stem cells and a serrated colorectal cancer transcriptional signature in organoids

Letourneur, D.; Bergsten, E.; Raynaud, N.; Mondy, J.; Nigro, G.; Tsoumtsa Meda, L. L.; Vaysse, A.; Descorps-Declere, S.; Yoshida, A.; Stefani, C.; Sobhani, I.; Lemichez, E.; Mettouchi, A.

2025-10-04 cancer biology
10.1101/2025.10.02.680056 bioRxiv
Show abstract

Mechanistic insights are essential to understand how gut microbiota pathobionts contribute to tumorigenesis, given the mounting evidence linking them to colorectal cancer. We report a higher prevalence of the Rho GTPases-targeting cnf1 toxin gene from Escherichia coli in the microbiota of early-stage, proximal colorectal cancer. Comparative gene set enrichment analysis reveals a concordant serrated pathway signature between colorectal cancer tissue of patients colonized with cnf1+ bacteria and CNF1-treated mouse intestinal organoids. RNA sequencing of organoids shows that CNF1 induces a fetal-like transcriptional reprogramming. Using integrated approaches, we demonstrate that CNF1 reprograms Lgr5 stem cells into a Ly6a/Sca-1 fetal-like state, that exhibits enhanced stemness potential. This reprogramming is preceded by a Yap/Taz-driven early transcriptional program and nuclear translocation of Yap. Functional analyses identify a RhoA/Rock-Yap/Taz-dependent transition to Ly6a/Sca-1 stem cells, highlighting a mechanistic link between bacterial effectors and stem cell plasticity in colorectal tumorigenesis.

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