The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Université Côte D'Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, France.
Nat Commun. 2020 May 6;11(1):2228. doi: 10.1038/s41467-020-16070-6.
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.
细胞竞争是一种新兴的原则，它可以消除次优或潜在危险的细胞。为了检测“不适宜”的细胞，需要将它们的竞争状态与组织内细胞的集体适应性进行比较。在这里，我们报告 NMDA 受体控制着果蝇翅膀盘状上皮细胞和 Myc 超级竞争者的细胞竞争。虽然 NMDA 受体亚基 NR2 的克隆耗竭会通过 TNF/Eiger>JNK 信号通路导致其迅速消除，但局部过表达 NR2 会导致 NR2 细胞获得超级竞争者样行为，使它们能够通过克隆扩张超越组织，这种扩张导致并依赖于周围细胞的死亡。一致地，Myc 克隆利用 NR2 为它们提供超级竞争者状态。从机制上讲，我们发现“失败者”细胞中的 JNK>PDK 信号轴重新编程了它们的代谢，促使它们产生并将乳酸转移给胜利者。防止乳酸从失败者向胜利者转移会消除 NMDAR 介导的细胞竞争。我们的研究结果表明，NMDAR 在监测组织适应性方面具有功能上的重新利用。
