Autocrine glutamate signaling drives cell competition in Drosophila

Cell competition is an evolutionary 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 the 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 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.

细胞竞争（Cell competition）是一种进化保守的质量控制过程，可清除亚最优或具有潜在危险的细胞。尽管差异代谢状态是细胞竞争的直接驱动因子，但这类代谢状态如何跨组织被感知的机制仍不明晰。本研究证实，囊泡谷氨酸转运蛋白（vesicular glutamate transporter, VGlut）及自分泌谷氨酸信号通路，是果蝇上皮组织中细胞竞争与Myc驱动的超级竞争所必需的核心调控通路。我们发现，在竞争环境下，谷氨酸激活的VGlut→N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor, NMDAR）→钙/钙调蛋白依赖性蛋白激酶Ⅱ（CaMKII）→CrebB信号通路的缺失，会通过自分泌诱导肿瘤坏死因子（Tumor Necrosis Factor, TNF）的表达，触发失败者细胞状态及细胞死亡。这进而会激活肿瘤坏死因子受体（TNFR），触发c-Jun氨基末端激酶（JNK）的活化，介导失败者细胞的清除，并引发依赖于丙酮酸脱氢酶激酶（PDK）与乳酸脱氢酶（LDH）的代谢重编程。抑制半胱天冬酶（caspases）或阻断失败者细胞向邻近细胞转运乳酸，均可使细胞竞争过程完全失效。此外，在果蝇癌前病变模型中，过表达Myc的细胞克隆会劫持这一信号通路，从而获得超级竞争者的身份。靶向干预谷氨酸信号通路，可将Myc阳性的超级竞争者克隆转化为失败者克隆，这为限制更具适应性的克隆的进化提供了全新的治疗契机。