VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers

Abstract

// Rubén A. Bartolomé 1 , Sofía Torres 1 , Soledad Isern de Val 1 , Beatriz Escudero-Paniagua 1 , Eva Calviño 1 , Joaquín Teixidó 1 and J. Ignacio Casal 1 1 Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu, Madrid, Spain Correspondence to: J. Ignacio Casal, email: // Keywords : VE-cadherin, RGD motif, metastasis, melanoma, breast cancer Received : November 08, 2016 Accepted : November 14, 2016 Published : December 09, 2016 Abstract We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.