Abstract LB-515: Guanine nucleotide exchange factor Dock7 expression is increased in human glioblastoma and mediates tumor cell invasion.

Abstract

Abstract Glioblastoma multiforme (GBM), the most common and deadly adult brain malignancy, is an incurable disease with an average life expectancy of 14 months following diagnosis. GBM morbidity is primarily due to its rapid growth, neovascularization and invasion throughout the brain. Recently, anti-VEGF therapies approved in this indication have paradoxically been shown to stimulate the invasive behavior of GBM. Members of the Rho family of small GTPases have been established as important mediators of GBM cell invasion. These proteins are activated by guanine nucleotide exchange factors (GEFs). In the current study, we sought to identify GEFs that are up-regulated in high-grade glioma and which may be of functional importance in human GBM. In this study we have shown that that Dock7, a GEF that can mediate signaling of Rac1 and Cdc42 Rho GTPases is up-regulated in human GBM tissue in comparison with normal brain. We have further demonstrated that Dock7 silencing by RNA-interference inhibits invasion of U87 and SNB19 GBM cells into ex vivo brain slices. Dock7 silencing inhibits Hepatocyte Growth Factor (HGF)-induced cell invasion in a 3D in vitro assay. HGF is known to strongly stimulate GBM cell invasiveness and both HGF and its receptor c-MET have been shown to be up-regulated in high- versus low-grade gliomas. Interestingly, we have also shown that Dock7 binds to c-MET in an HGF-dependent manner and that this interaction requires the GAB1 adaptor protein. Dock7 silencing reduced HGF-induced activation of Rac1 and consistent with this, we have shown that Dock7 silencing results in the inhibition of HGF-induced lamellipodia formation in GBM cells. Finally Dock7 was shown to be activated in an HGF-dependant manner, using Rac1-G15A pull-down assay. In summary, our data suggests a role for Dock7 in GBM cell invasion thus, Dock7 may present a potential therapeutic target in the management of invasive GBM, in particular in the adjuvant setting in combination with anti-VEGF therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-515. doi:1538-7445.AM2012-LB-515