RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis

• Published in: The Journal of clinical investigation Vol. 132; no. 2
• Main Authors: Yue, Zhiying, Niu, Xin, Yuan, Zengjin, Qin, Qin, Jiang, Wenhao, He, Liang, Gao, Jingduo, Ding, Yi, Liu, Yanxi, Xu, Ziwei, Li, Zhenxi, Yang, Zhengfeng, Li, Rong, Xue, Xiwen, Gao, Yankun, Yue, Fei, Zhang, Xiang H.-F, Hu, Guohong, Wang, Yi, Li, Yi, Chen, Geng, Siwko, Stefan, Gartland, Alison, Wang, Ning, Xiao, Jianru, Liu, Mingyao, Luo, Jian
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 15.01.2022
• Subjects: Bone cancer; Cell receptors; Cellular signal transduction; Development and progression; Genetic aspects; Health aspects; Metastasis; Osteoclasts (Biology); China
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI144579.

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through G[[alpha].sub.q] and [beta]-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor-related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.