Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR.

There are limited methods to stably analyze the interactions between cancer cells and glial cells in vitro, 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.

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Declaration of interests S.Y. obtained commercial research grants from AstraZeneca, Chugai Pharm, and Boehringer Ingelheim and has received speaking honoraria from AstraZeneca, Chugai Pharma, and Boehringer-Ingelheim. Other authors declare no competing interests. M.N. obtained commercial research grants from Daiichi Sankyo, Eisai, Chugai, Shionogi, Mitsubishi Tanabe, Kyowa Kirin, Otsuka, and Stryker, and has received speaking honoraria from Daiichi Sankyo, Eisai, Pfizer, Novocure, and Chugai.