Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, over-expression of the metabotropic glutamate receptor GRM1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the MAPK and PI3K/AKT pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of IL-8 and VEGF, due to GRM1-mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in post-treatment as compared to pre-treatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers pro-angiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients.
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
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