Winners vs Losers: The glutamate-NMDAR signalling axis in the regulation of cell fitness

Abstract

Cell competition is an evolutionary conserved quality control process that eliminates suboptimal or potentially dangerous cells. For ‘unfit’ cells to be detected, their competitive status needs to be compared to the collective fitness of cells within the tissue. Here, I demonstrate that the vesicular glutamate transporter VGlut, and autocrine glutamate signalling, are required for cell competition and Myc-driven super-competition in epithelia. I find that autocrine secretion of glutamate stimulates NMDAR-mediated activation of the CaMKII, PKA and CrebB signalling axis, thereby suppressing loser status and cell death under competitive settings. Accordingly, upon clonal loss of autocrine glutamate signalling, cells acquire loser status via the induction of TNF. This in turn drives autocrine TNFR-mediated activation of JNK that triggers loser cell elimination. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbours removes the fitness disparity and nullifies cell competition. Further, in a Drosophila model for premalignant cancer, clones that overexpress the Myc proto-oncogene co-opt the VGlut>extracellular glutamate>NMDAR>CaMKII, PKA>CrebB signalling circuit to acquire super-competitor status and subdue their wild-type neighbours. Targeting glutamate signalling converts Myc ‘super-competitor’ clones into ‘losers’, highlighting new therapeutic opportunities to restrict the evolution of fitter clones.