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

• F. nucleatum (Fn) adhesin FadA binds E-cadherin and promotes CRC cell proliferation
• A peptide from the FadA-binding region of E-cadherin prevents Fn-mediated carcinogenesis
• FadA promotes inflammation and E-cadherin-mediated CRC tumor growth in xenograft mice
• Tissues from human adenomas and adenocarcinomas have elevated fadA gene levels

SummaryFusobacterium 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.