Regulation of tumor released exosomes and glutamatergic signaling

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 DESCRIPTION (provided by applicant): The incidence of cutaneous melanoma is going up faster than almost any other tumor type in the US and remains one of the most challenging malignancies to treat. Surgical intervention prior to the onset of metastatic spread is a key facto for reducing mortality and morbidity in patients with melanoma, yet, metastases still occur in many patients, resulting in a rather poor prognosis. While there has been some recent success in the development of targeted therapies such as vemurafenib in melanomas that carry the BRAFV600E mutation, the response to these therapies appears transient and treatment is complicated by the development of secondary tumors. Modern immunotherapies such as anti-CTLA-4 or anti-PD1 antibodies have also shown promise with 20%-30% response rates, modest increases in overall survival, and a generally favorable toxicity profile. However, the majority of patients with advance melanoma do not derive lasting benefit from these therapies and new approaches are still needed. Our group demonstrated the etiological role of ectopic expression of a murine neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in mouse melanocytes in genetically modified transgenic mouse models. Aberrant expression of the human form of GRM1 was also observed in H95% of human melanoma cell lines and H65% of biopsy samples but is not expressed by normal human melanocytes, suggesting it is involved in melanomagenesis. Our team has extensive experience and a track record working together in translating results from the bench to the clinic and in the current application our goal is to characterize the mechanisms by which microvesicle (exosomes) are produced in GRM1-expressing melanoma cells and how this contributes to melanoma metastasis. The "Melanoma exosomal messenger system" was first proposed by Hood and colleagues in 2009 as one of the ways melanoma cells communicate within the local tumor microenvironment to enhance tumor cell dissemination. In this application, we will use both genetic and pharmacological approaches to assess the dependence of melanoma cells on active GRM1 and its ligand, glutamate, to produce exosomes. We will also use archived pre-and post-treatment clinical samples from three different trials that incorporated riluzole, a negative modulator of glutamate signaling, to search for a possible correlation between exosome production and biologic response in patients with melanoma. The final Aim will examine riluzole as a chemopreventive agent using our spontaneous metastasis melanoma mouse model that mimics human disease and permits analysis of both early and late stages of metastasis. Our main goal is to unravel the mechanisms responsible for exosome formation in melanoma and to determine what role exosomes play in melanoma progression in order to inform the design of future clinical trials.