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

Kojiro Ishibashi¹, Toshiya Ichinose², Riki Kadokawa¹, Ryo Mizutani¹, Sadahiro Iwabuchi³, Sumihito Togi⁴, Hiroki Ura⁴, Shoichiro Tange⁵, Keiko Shinjo⁶, Jun Nakayama⁷, Shigeki Nanjo⁸, Yo Niida⁴, Yutaka Kondo⁶, Shinichi Hashimoto³, Erik Sahai⁹, Seiji Yano¹⁰, Mitsutoshi Nakada², Eishu Hirata¹¹

Affiliations

¹ Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan.
² Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan.
³ Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Wakayama, Japan.
⁴ Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Ishikawa, Japan; Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.
⁵ Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan.
⁶ Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan.
⁷ Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka 541-8567, Osaka, Japan.
⁸ Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan; Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan.
⁹ Tumor Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
¹⁰ Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan; Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan.
¹¹ Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan. Electronic address: ehirata@staff.kanazawa-u.ac.jp.

PMID: 38309264
DOI: 10.1016/j.devcel.2024.01.010

Free article

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

Kojiro Ishibashi et al. Dev Cell. 2024.

Free article

. 2024 Mar 11;59(5):579-594.e6.

doi: 10.1016/j.devcel.2024.01.010. Epub 2024 Feb 2.

Authors

Affiliations

¹ Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan.
² Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan.
³ Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Wakayama, Japan.
⁴ Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada 920-0293, Ishikawa, Japan; Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan.
⁵ Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, Sapporo 060-8556, Hokkaido, Japan.
⁶ Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan.
⁷ Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka 541-8567, Osaka, Japan.
⁸ Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan; Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan.
⁹ Tumor Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
¹⁰ Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa 920-8641, Ishikawa, Japan; Division of Medical Oncology, Cancer Research Institute of Kanazawa University, Kanazawa 920-8641, Ishikawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan.
¹¹ Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Ishikawa, Japan. Electronic address: ehirata@staff.kanazawa-u.ac.jp.

PMID: 38309264
DOI: 10.1016/j.devcel.2024.01.010

Abstract

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.

Keywords: EGFR; PRICKLE1; REST; Wnt-5a; astrocyte; brain metastasis; cancer-glia interaction; glial cell culture; lung cancer; mGluR1.

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Conflict of interest statement

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.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous