Fusobacterium nucleatum Promotes Colorectal Carcinogenesis by Modulating E-Cadherin/β-Catenin Signaling via its FadA Adhesin

TLDR

Fusobacterium nucleatum has been linked to colorectal cancer, yet causality and mechanisms remain unclear. The study seeks to elucidate how Fn drives colorectal cancer and to establish FadA as a diagnostic and therapeutic target. The authors demonstrate that Fn’s FadA adhesin binds E‑cadherin, activates β‑catenin signaling, and induces oncogenic and inflammatory responses that stimulate CRC cell growth. They mapped the FadA‑E‑cadherin binding site to an 11‑amino‑acid motif, showed that a synthetic peptide from this motif blocks FadA‑induced CRC growth and inflammation, and found that fadA expression is 10–100× higher in adenomas and adenocarcinomas and correlates with upregulation of oncogenic and inflammatory genes.

Abstract

Fusobacterium nucleatum (Fn) has been associated with colorectal cancer (CRC), but causality and underlying mechanisms remain to be established. We demonstrate that Fn adheres to, invades, and induces oncogenic and inflammatory responses to stimulate growth of CRC cells through its unique FadA adhesin. FadA binds to E-cadherin, activates β-catenin signaling, and differentially regulates the inflammatory and oncogenic responses. The FadA-binding site on E-cadherin is mapped to an 11-amino-acid region. A synthetic peptide derived from this region of E-cadherin abolishes FadA-induced CRC cell growth and oncogenic and inflammatory responses. The fadA gene levels in the colon tissue from patients with adenomas and adenocarcinomas are >10–100 times higher compared to normal individuals. The increased FadA expression in CRC correlates with increased expression of oncogenic and inflammatory genes. This study unveils a mechanism by which Fn can drive CRC and identifies FadA as a potential diagnostic and therapeutic target for CRC.