Winners vs Losers: The glutamate-NMDAR signalling axis in the regulation of cell fitness
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Date
2024-05-21ICR Author
Author
Meier P
Castilho Soares, C
Meier, P
Type
Thesis or Dissertation
Metadata
Show full item recordAbstract
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.
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Research team
Cell Death and Immunity
Language
eng
License start date
2024-05-21
Citation
2024
Publisher
Institute of Cancer Research (University Of London)