Vasculogenic Mimicry (VM) refers to the capacity to form blood network from aggressive cancers cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study we demonstrated that VE-Cadherin and its phosphorylation at Y658 of VE-Cadherin modulated kaiso-dependent gene expression (CCND1 and Wnt 11) by regulation of Focal Adhesion kinase (FAK). In the present study, using a proteomic approach, we have found that β-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VE-cadherin upon FAK resulted in VE-Cadherin/β-catenin complex dissociation, increased β-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses β-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of β-catenin and tumor growth reduction in vivo experiments. In vivo, the combined treatment with the FAK inhibitor PF271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth respect to the single treatment. In conclusion, the aberrant expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation of Y658 by FAK, favors the induction of the aggressive VM phenotype through its interaction with β-catenin to VE-Cadherin and by enhancing TCF-4 genes-dependent transcription