Abstract
Cell competition is an emerging principle 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 a tissue. Here we report that the NMDA receptor controls cell competition of epithelial cells and Myc supercompetitors in the Drosophila wing disc. While clonal depletion of the NMDA receptor subunit NR2 results in their rapid elimination via the TNF/Eiger>JNK signalling pathway, local over-expression of NR2 causes NR2 cells to acquire supercompetitor-like behaviour that enables them to overtake the tissue through clonal expansion that causes, but also relies on, the killing of surrounding cells. Consistently, NR2 is utilised by Myc clones to provide them with supercompetitor status. Mechanistically, we find that the JNK>PDK signalling axis in ‘loser’ cells reprograms their metabolism, driving them to produce and transfer lactate to winners. Preventing lactate transfer from losers to winners abrogates NMDAR-mediated cell competition. Our findings demonstrate a functional repurposing of NMDAR in the surveillance of tissue fitness.
Highlights
Cell competition is an emerging principle that eliminates suboptimal or potentially dangerous cells
We find that the JNK>Pyruvate Dehydrogenase Kinase (PDK) signalling axis in ‘loser’ cells results in phosphorylation and inactivation of Pyruvate Dehydrogenase (PDH), the enzyme that converts pyruvate to Acetyl-CoA to fuel the tricarboxylic acid (TCA) in the mitochondria
Our data indicate that the NMDA receptor NR2 influences the competitive behaviour of epithelia cells and Myc supercompetitors in the Drosophila wing disc
Summary
Cell competition is an emerging principle that eliminates suboptimal or potentially dangerous cells. While clonal depletion of the NMDA receptor subunit NR2 results in their rapid elimination via the TNF/Eiger>JNK signalling pathway, local over-expression of NR2 causes NR2 cells to acquire supercompetitor-like behaviour that enables them to overtake the tissue through clonal expansion that causes, and relies on, the killing of surrounding cells. We find that the JNK>PDK signalling axis in ‘loser’ cells (lower NMDAR) results in phosphorylation and inactivation of PDH, the enzyme that converts pyruvate to Acetyl-CoA to fuel the TCA in the mitochondria. In such loser cells, phospho-dependent inactivation of PDH causes mitochondrial shutdown and metabolic reprogramming, loser cells produce and secrete lactate to winners. Together our data are consistent with the notion that NMDAR underpins cell competition and that targeting NMDAR converts Myc supercompetitor clones into superlosers
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