VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry Delgado Bellido, Daniel Zamudio Martínez, Esteban Fernández Cortés, Mónica Herrera-Campos, Ana Belén Olmedo-Pelayo, Joaquin Jordán Perez, Carmen Expósito Hernández, José de Álava, Enrique Amaral, Ana Teresa O´Valle, Francisco Díaz García, José Ángel Oliver, F. Javier Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer 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 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, 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 VEcadherin upon FAK disabling 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 concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of β-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription. 2024-10-02T10:42:57Z 2024-10-02T10:42:57Z 2023-02-08 journal article Delgado Bellido, D. et. al. Cell Death Dis 14, 135 (2023). [https://doi.org/10.1038/s41419-023-05666-7] https://hdl.handle.net/10481/95423 10.1038/s41419-023-05666-7 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Springer Nature