<i>Fusobacterium nucleatum</i> Promotes the Growth and Metastasis of Colorectal Cancer by Activating E‐Cadherin/Krüppel‐Like Factor 4/Integrin α5 Signaling in a Calcium‐Dependent Manner

Gut microbiota and integrins are known to contribute to colorectal cancer (CRC), but whether they interact has been unclear. Here, we provided evidence that <i>Fusobacterium nucleatum</i> upregulated integrin α5 (ITGA5) in CRC in both human patients and murine models. Knocking down <i>ITGA5</i> in CRC cells weakened the ability of <i>F. nucleatum</i> to stimulate their malignant characteristics. <i>Fusobacterium nucleatum</i> increased intracellular Ca²⁺ concentration, which in turn promoted interaction between E-cadherin and Krüppel-like factor 4 (KLF4), resulting in KLF4 phosphorylation and translocation in the nucleus, where it induced <i>ITGA5</i> transcription and activated the downstream signaling. Knocking down E-cadherin or chelating Ca²⁺ with BAPTA-AM antagonized the impact of <i>F. nucleatum</i> on KLF4, whereas knocking down <i>KLF4</i> or chelating Ca²⁺ antagonized the bacteria's oncogenic role. Knocking down <i>KLF4</i> or <i>ITGA5</i> attenuated <i>F. nucleatum-</i>induced growth of patient-derived organoids, subcutaneous xenografts, and orthotopic tumors, as well as liver metastasis in nude mice. Integrin α5 antibody antagonized the oncogenic role of <i>F. nucleatum</i> in vitro and in vivo. These findings suggest that <i>F. nucleatum</i> promotes the growth and metastasis of CRC by activating E-cadherin/KLF4/integrin α5 signaling in a Ca²⁺-dependent manner.