Autocrine glutamate signaling drives cell competition in Drosophila.
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Embargo End Date
ICR Authors
Authors
Soares, CC
Rizzo, A
Maresma, MF
Meier, P
Rizzo, A
Maresma, MF
Meier, P
Document Type
Journal Article
Date
2024-11-18
Date Accepted
2024-06-26
Abstract
Cell competition is an evolutionarily conserved quality control process that eliminates suboptimal or potentially dangerous cells. Although differential metabolic states act as direct drivers of competition, how these are measured across tissues is not understood. Here, we demonstrate that vesicular glutamate transporter (VGlut) and autocrine glutamate signaling are required for cell competition and Myc-driven super-competition in the Drosophila epithelia. We find that the loss of glutamate-stimulated VGlut>NMDAR>CaMKII>CrebB signaling triggers loser status and cell death under competitive settings via the autocrine induction of TNF. This in turn drives TNFR>JNK activation, triggering loser cell elimination and PDK/LDH-dependent metabolic reprogramming. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbors nullifies cell competition. Further, in a Drosophila model for premalignancy, Myc-overexpressing clones co-opt this signaling circuit to acquire super-competitor status. Targeting glutamate signaling converts Myc "super-competitor" clones into "losers," highlighting new therapeutic opportunities to restrict the evolution of fitter clones.
Citation
Developmental Cell, 2024, pp. S1534-5807(24)00400-3 -
Source Title
Developmental Cell
Publisher
CELL PRESS
ISSN
1534-5807
eISSN
1878-1551
Collections
Research Team
Cell Death and Immunity