There are limited methods to stably analyze the interactions between cancer cells and glial cells , which hinders our molecular understanding. Here, we develop a simple and stable culture method of mouse glial cells, termed mixed-glial culture on/in soft substrate (MGS), which serves well as a platform to study cancer-glia interactions. Using this method, we find that human lung cancer cells become overly dependent on metabotropic glutamate receptor 1 (mGluR1) signaling in the brain microenvironment. Mechanistically, interactions with astrocytes induce mGluR1 in cancer cells through the Wnt-5a/prickle planar cell polarity protein 1 (PRICKLE1)/RE1 silencing transcription factor (REST) axis. Induced mGluR1 directly interacts with and stabilizes the epidermal growth factor receptor (EGFR) in a glutamate-dependent manner, and these cells then become responsive to mGluR1 inhibition. Our results highlight increased dependence on mGluR1 signaling as an adaptive strategy and vulnerability of human lung cancer brain metastasis.

中文翻译：

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星形胶质细胞诱导的 mGluR1 通过谷氨酸依赖性 EGFR 稳定激活人肺癌脑转移

稳定分析癌细胞和神经胶质细胞之间相互作用的方法有限，这阻碍了我们的分子理解。在这里，我们开发了一种简单而稳定的小鼠胶质细胞培养方法，称为软基质上/软基质内混合胶质细胞培养（MGS），它可以作为研究癌症-胶质细胞相互作用的平台。使用这种方法，我们发现人类肺癌细胞过度依赖大脑微环境中的代谢型谷氨酸受体 1 (mGluR1) 信号。从机制上讲，与星形胶质细胞的相互作用通过 Wnt-5a/棘平面细胞极性蛋白 1 (PRICKLE1)/RE1 沉默转录因子 (REST) 轴在癌细胞中诱导 mGluR1。诱导的 mGluR1 以谷氨酸依赖性方式直接与表皮生长因子受体 (EGFR) 相互作用并稳定表皮生长因子受体 (EGFR)，然后这些细胞对 mGluR1 抑制产生反应。我们的结果强调了对 mGluR1 信号传导作为一种适应性策略的依赖性增加以及人类肺癌脑转移的脆弱性。