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. [Display omitted] •MGS serves well as a platform to study cancer-glia interactions•Astrocyte-derived Wnt-5a induces mGluR1 in cancer cells•mGluR1 stabilizes EGFR and activates ERK in a glutamate-dependent manner•mGluR1 could be a target for EGFR-mutant lung cancer brain metastasis Ishibashi et al. report that astrocyte-derived Wnt-5a induces mGluR1 expression in brain metastatic lung cancer cells, which directly interacts with and stabilizes EGFR in a glutamate-dependent manner, leading to activation of the MAPK pathway and progression of brain metastasis.