VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry

• Published in: Cell death & disease Vol. 14; no. 2; p. 135
• Main Authors: Delgado-Bellido, Daniel, Zamudio-Martínez, Esteban, Fernández-Cortés, Mónica, Herrera-Campos, Ana Belén, Olmedo-Pelayo, Joaquin, Perez, Carmen Jordán, Expósito, José, de Álava, Enrique, Amaral, Ana Teresa, Valle, Francisco O', Diaz, Angel Garcia, Oliver, F J
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 17.02.2023; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Angiogenesis; Antiangiogenic agents; beta Catenin - genetics; beta Catenin - metabolism; Bevacizumab; c-Myc protein; Cadherins; Cadherins - genetics; Cadherins - metabolism; Cooperation; Endothelial cells; Endothelial Cells - metabolism; Focal adhesion kinase; Gene expression; Kinases; Melanoma; Melanoma - pathology; Metastases; Microenvironments; Mimicry; Myc protein; Phenotypes; Phosphorylation; Proteomics; Skin cancer; Transcription Factor 4 - metabolism; Tumors; Uveal Neoplasms - pathology; Wnt protein; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05666-7

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 VE-cadherin 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.