Targeting glutamate metabolism in melanoma

TL;DR

This study reveals that targeting glutamate metabolism, specifically its secretion and biosynthesis, can effectively suppress melanoma growth driven by GRM1 activation, offering a promising therapeutic approach.

Contribution

It identifies glutamate metabolism as a therapeutic target in melanoma and demonstrates that combined inhibition of glutamate secretion and biosynthesis suppresses tumor growth.

Findings

Elevated plasma glutamate levels are associated with metastatic melanoma.

GRM1-positive melanoma cells utilize glycolytic carbon to produce glutamate.

Combined inhibition of glutamate secretion and biosynthesis suppresses tumor growth.

Abstract

The glutamate metabotropic receptor 1 (GRM1) drives oncogenesis when aberrantly activated in melanoma and several other cancers. Metabolomics reveals that patient-derived xenografts with GRM1-positive melanoma tumors exhibit elevated plasma glutamate levels associated with metastatic melanoma in vivo. Stable isotope tracing and GCMS analysis determined that cells expressing GRM1 fuel a substantial fraction of glutamate from glycolytic carbon. Stimulation of GRM1 by glutamate leads to activation of mitogenic signaling pathways, which in turn increases the production of glutamate, fueling autocrine feedback. Implementing a rational drug-targeting strategy, we critically evaluate metabolic bottlenecks in vitro and in vivo. Combined inhibition of glutamate secretion and biosynthesis is an effective rational drug targeting strategy suppressing tumor growth and restricting tumor bioavailability of glutamate.