Abstract B39: Inhibiting endothelial FAK activity blocks tumor cell extravasation

Abstract

Abstract Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that modulates signaling from growth factor, integrin, and cadherin receptors in both tumor and stromal cells. Pharmacological FAK inhibition prevents tumor growth and metastasis, but the target cell action associated with this remains unclear. Recent studies using an inducible endothelial cell (EC) specific FAK kinase-inactive knock-in mouse model revealed that vascular endothelial growth factor (VEGF) increased cell permeability was dependent upon FAK activity. VEGF triggers conformational FAK activation, binding of FAK to the cytoplasmic tail of VE-cadherin, and FAK-dependent phosphorylation of adherens junction proteins regulating vascular integrity. Here we provide genetic and pharmacological support for the importance for FAK activity in mediating direct VE-cadherin tyrosine (Y) 658 phosphorylation in tumor-associated ECs in vivo. In cell culture, VEGF-induced transmigration of tumor cells through an EC barrier is prevented by genetic EC-specific FAK inhibition or reconstitution of Y658F VE-cadherin within null ECs. In mice, VEGF enhances circulating tumor cell extravasation within the lungs and this is prevented by inducible knockin of kinase-dead FAK within ECs. These studies provide a mechanistic foundation for the importance of FAK and VE-cadherin interactions in the regulation of adherens junction stability and support future evaluation of FAK inhibitors in the treatment of metastatic cancer. Citation Format: Chris Jean, Ju-Ock Nam, Xiao-Lei Chen, Sean Uryu, Isabelle Tancioni, Christine Lawson, Kristy K. Ward, Colin T. Walsh, Majid Ghassemian, Patric Turowski, Elisabetta Dejana, Sara M. Weis, David A. Cheresh, David D. Schlaepfer. Inhibiting endothelial FAK activity blocks tumor cell extravasation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B39.