Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor secreted angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial due to the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with three novel binding partners, integrin α5β1, VEcadherin and claudin-5, in a temporally sequential manner, thus facilitating metastasis. We showed that cANGPTL4 binds and activates integrin α5β1-mediated Rac1/PAK signaling to weaken cell-cell contacts. cANGPTL4 subsequently associated with and declustered VE-cadherin and claudin-5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delayed vascular disruption. In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated lung metastasis in mice. Thus, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies.Les perturbations vasculaires induites par des interactions entre des facteurs de perméabilité secrétés par une tumeur et des protéines adhésives sur des cellules endothéliales facilitent la métastase. Le rôle de l'angiopoïétine-like 4 secrétée par une tumeur (cANGPTL4) dans la porosité vasculaire et la métastase est controversé en raison de la compréhension insuffisante de la façon dont cANGPTL4 module l'intégrité vasculaire. Ici, on montre que cANGPTL4 est à l'origine de la perturbation de la continuité endothéliale par une interaction directe avec trois nouveaux partenaires de liaison, l'intégrine α5β1, la VE-cadhérine et la claudine-5, de man
