Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth.

Direct and paracrine neuron-cancer interactions govern tumor development and progression. While neuron-elaborated neurotransmitters, like glutamate, support neoplastic growth, the mechanism underlying tumor intracellular mitogenic signaling and proliferation remains an unresolved question in cancer neuroscience. Herein, we discover that glutamate receptor (GluR) stimulation phosphorylates sarcoma proto-oncogene (Src) to activate platelet-derived growth factor (PDGF) receptor-α (PDGFRα)-dependent extracellular-regulated kinase (ERK) signaling and drive glioma growth. Using single-cell transcriptomic datasets and unique laboratory-generated humanized models of the most common brain tumor in children (pilocytic astrocytoma [PA]), we identify glutamatergic pathway enrichment in tumor cells, where glutamate increases PA proliferation without changing membrane depolarization. Aberrant GRID2 and GRIK3 GluR expression increases rat sarcoma (RAS)/ERK signaling by selective Src-mediated PDGFRα activation. Moreover, genetic or pharmacologic GRID2/GRIK3 and PDGFRA inhibition reduce PDGFRα/RAS/ERK activation, PA cell proliferation, and PA xenograft growth. Taken together, these observations establish a conceptual framework for understanding similar neurotransmitter dependencies in other cancers.