细胞竞争是一种进化上保守的质量控制过程，可以消除次优或潜在危险的细胞。尽管不同的代谢状态是竞争的直接驱动因素，但如何在组织中测量这些状态尚不清楚。在这里，我们证明了果蝇上皮细胞竞争和 Myc 驱动的超级竞争需要囊泡谷氨酸转运蛋白 (VGlut) 和自分泌谷氨酸信号传导。我们发现，谷氨酸刺激的 VGlut>NMDAR>CaMKII>CrebB 信号传导的丧失会通过 TNF 的自分泌诱导，在竞争环境下触发失败者状态和细胞死亡。这反过来又驱动 TNFR>JNK 激活，触发失败细胞消除和 PDK/LDH 依赖性代谢重编程。抑制半胱天冬酶或阻止失败者细胞将乳酸转移给邻居细胞可以消除细胞竞争。此外，在癌前病变的果蝇模型中，Myc 过表达克隆利用该信号通路来获得超级竞争者状态。靶向谷氨酸信号传导将 Myc“超级竞争者”克隆转化为“失败者”，凸显了限制更适合克隆进化的新治疗机会。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.