Abstract 3889: GRM1 over-expression in melanoma cells promotes microvesicle formation which functions in stimulating angiogenesis.

Abstract

Our group has reported that metabotropic glutamate receptor 1 (GRM1) as an oncogene and a potential therapeutic target for melanoma. More than 60% of human melanoma expresses GRM1, while normal melanocytes do not. In a Phase-0 trial of riluzole (an oral inhibitor of GRM1) in patients with advanced melanoma we showed suppression of the PI3K/AKT and MAPK pathways in melanoma specimens in 34% of the patients. Our group found that enhanced expression of GRM1 in a subclone of a melanoma cell line (UACC903) that normally expresses low levels of GRM1 stimulated angiogenesis via activation of the AKT-mTOR-HIF1-IL8, VEGF signaling pathway. Increasing GRM1 expression promoted membrane blebbing (a phenomenon that appears to lead to microvesicle formation) and riluzole treatment inhibited this effect. Suppression of GRM1 expression using an inducible siRNA construct inhibits the blebbing phenomena and microvesicle formation. Therefore, we hypothesize that GRM1 expression promotes microvesicle formation that may be involved in stimulating angiogenesis and tumor progression. Through electron-microscope and flow cytometry analysis, we have confirmed that increased GRM1 expression enhanced microvesicle secretion into the medium in cell culture and that knocking down GRM1 expression significantly reduced the quantity of microvesicle secretion. Furthermore, intra-tumor injection of collected microvesicles into two different melanoma xenograft tumors (UACC903 and C8161) demonstrated that the microvesicles formed from high GRM1 expressing cells promoted tumor growth and angiogenesis. We also showed that microvesicles from high GRM1 expressing cells increased endothelial cell proliferation exhibited measured using a BrdU incorporation assay. Our preliminary data demonstrate that GRM1 expression promotes microvesicle formation and that these microvesicles are associated with angiogenesis. Research on the molecular events associated with the phenomenon is ongoing. Citation Format: Jasmine J. Koo, Yu Wen, Jiadong Li, Suzie Chen, James Goydos. GRM1 over-expression in melanoma cells promotes microvesicle formation which functions in stimulating angiogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3889. doi:10.1158/1538-7445.AM2013-3889