The Journal of Clinical Investigation (Jan 2022)

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

  • Zhiying Yue,
  • Xin Niu,
  • Zengjin Yuan,
  • Qin Qin,
  • Wenhao Jiang,
  • Liang He,
  • Jingduo Gao,
  • Yi Ding,
  • Yanxi Liu,
  • Ziwei Xu,
  • Zhenxi Li,
  • Zhengfeng Yang,
  • Rong Li,
  • Xiwen Xue,
  • Yankun Gao,
  • Fei Yue,
  • Xiang H.-F. Zhang,
  • Guohong Hu,
  • Yi Wang,
  • Yi Li,
  • Geng Chen,
  • Stefan Siwko,
  • Alison Gartland,
  • Ning Wang,
  • Jianru Xiao,
  • Mingyao Liu,
  • Jian Luo

Journal volume & issue
Vol. 132, no. 2

Abstract

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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 Gαq and β-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.

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