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

作者：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^*

来源：Journal of Clinical Investigation, 2022, 132(2): e144579.

DOI：10.1172/JCI144579

• BREAST-CANCER METASTASIS
• FACTOR-KAPPA-B
• RECEPTOR ACTIVATOR
• CELLS
• WNT
• MIGRATION
• LIGAND
• DIFFERENTIATION
• DENOSUMAB
• LUNG

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 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.

• 单位
  上海交通大学; 同济大学; 中国科学院