Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma

SIMPLE SUMMARY: Out of all the skin cancers, melanoma is the most aggressive and dangerous form due to its high metastatic propensity. Patients with late-stage melanomas have poor prognosis as their five-year survival rate is only 27% while the survival rate for primary melanomas is 99%. Metastatic melanomas are resistant to most therapeutic approaches, progress quickly, and account for the majority of mortalities in melanoma patients. Melanomas like other cancers are driven by the dysregulation of the normal cellular networks that leads to uncontrolled cell proliferation, altered cellular metabolism and dissemination of tumor cells to distal organs. Our lab has described the oncogenic role of a normal neuronal receptor, Metabotropic Glutamate Receptor 1, that when aberrantly expressed in melanocytes leads to deregulated glutamatergic signaling in melanocytes. Activation of this receptor results in a cascade of disorders that promote cell transformation and tumor formation. Here we will explore the contribution of abnormal glutamatergic signaling to melanoma. ABSTRACT: Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and NF1. Our lab was the first to identify yet another driver of melanoma, Metabotropic Glutamate Receptor 1 (protein: mGluR1, mouse gene: Grm1, human gene: GRM1), upstream of the MAPK and PI3K/AKT pathways. Binding of glutamate, the natural ligand of mGluR1, activates MAPK and PI3K/AKT pathways and sets in motion the deregulated cellular responses in cell growth, cell survival, and cell metastasis. In this review, we will assess the proposed modes of action that mediate the oncogenic properties of mGluR1 in melanoma and possible application of anti-glutamatergic signaling modulator(s) as therapeutic strategy for the treatment of melanomas.