Journal Article

Crucial contribution of GPR56/ADGRG1, expressed by breast cancer cells, to bone metastasis formation

Sasaki, So‐ichiro, Baba, Tomohisa, Iwabuchi, Sadahiro, Tanabe, Yamato, Hayashi, Katsuhiro, Tsuchiya, Hiroyuki, Hayakawa, Yoshihiro, Hashimoto, Shinichi, Yamauchi, Akira, Mukaida, Naofumi, Zhang, Di

2021

Overview

From a mouse triple‐negative breast cancer cell line, 4T1, we previously established 4T1.3 clone with a high capacity to metastasize to bone after its orthotopic injection into mammary fat pad of immunocompetent mice. Subsequent analysis demonstrated that the interaction between cancer cells and fibroblasts in a bone cavity was crucial for bone metastasis focus formation arising from orthotopic injection of 4T1.3 cells. Here, we demonstrated that a member of the adhesion G‐protein–coupled receptor (ADGR) family, G‐protein–coupled receptor 56 (GPR56)/adhesion G‐protein–coupled receptor G1 (ADGRG1), was expressed selectively in 4T1.3 grown in a bone cavity but not under in vitro conditions. Moreover, fibroblasts present in bone metastasis sites expressed type III collagen, a ligand for GPR56/ADGRG1. Consistently, GPR56/ADGRG1 proteins were detected in tumor cells in bone metastasis foci of human breast cancer patients. Deletion of GPR56/ADGRG1 from 4T1.3 cells reduced markedly intraosseous tumor formation upon their intraosseous injection. Conversely, intraosseous injection of GPR56/ADGRG1‐transduced 4T1, TS/A (mouse breast cancer cell line), or MDA‐MB‐231 (human breast cancer cell line) exhibited enhanced intraosseous tumor formation. Furthermore, we proved that the cleavage at the extracellular region was indispensable for GPR56/ADGRG1‐induced increase in breast cancer cell growth upon its intraosseous injection. Finally, inducible suppression of Gpr56/Adgrg1 gene expression in 4T1.3 cells attenuated bone metastasis formation with few effects on primary tumor formation in the spontaneous breast cancer bone metastasis model. Altogether, GPR56/ADGRG1 can be a novel target molecule to develop a strategy to prevent and/or treat breast cancer metastasis to bone. GPR56/ADGRG1 expression conferred growth advantage on breast cancer cells in the bone cavity, thereby promoting bone metastasis formation.GPR56/ADGRG1 can be a novel target molecule to develop a strategy to treat breast cancer metastasis to bone.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Bone cancer / Bone growth / Bone marrow / bone metastasis / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - secondary / Bone tumors / Breast cancer / Cell growth / Cell Line, Tumor / Cell Proliferation - genetics / Cloning / Collagen / Collagen (type III) / Collagen Type III - metabolism / CRISPR / Epidermal growth factor / Experiments / Female / fibroblast / Fibroblasts / Gene Deletion / Gene expression / Gene Expression Regulation, Neoplastic / GPR56/ADGRG1 / Homeostasis / Humans / Injection / Insulin-like growth factors / Laboratory animals / Ligands / Mammary Neoplasms, Experimental - genetics / Mammary Neoplasms, Experimental - metabolism / Mammary Neoplasms, Experimental - pathology / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, SCID / mouse / Original / Pathogens / Protein Binding / Protein expression / Proteins / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / triple‐negative breast cancer / Tumor Burden - genetics / Tumor cells / Tumors