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RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2021 , DOI: 10.1172/jci144579 Zhiying Yue 1, 2 , Xin Niu 1 , Zengjin Yuan 1 , Qin Qin 1 , Wenhao Jiang 3 , Liang He 3 , Jingduo Gao 1 , Yi Ding 1 , Yanxi Liu 1 , Ziwei Xu 1 , Zhenxi Li 4 , Zhengfeng Yang 1, 2 , Rong Li 1 , Xiwen Xue 1 , Yankun Gao 5 , Fei Yue 6 , Xiang H-F Zhang 6 , Guohong Hu 7 , Yi Wang 5 , Yi Li 6 , Geng Chen 1 , Stefan Siwko 8 , Alison Gartland 9 , Ning Wang 9 , Jianru Xiao 4 , Mingyao Liu 1 , Jian Luo 1, 3
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2021 , DOI: 10.1172/jci144579 Zhiying Yue 1, 2 , Xin Niu 1 , Zengjin Yuan 1 , Qin Qin 1 , Wenhao Jiang 3 , Liang He 3 , Jingduo Gao 1 , Yi Ding 1 , Yanxi Liu 1 , Ziwei Xu 1 , Zhenxi Li 4 , Zhengfeng Yang 1, 2 , Rong Li 1 , Xiwen Xue 1 , Yankun Gao 5 , Fei Yue 6 , Xiang H-F Zhang 6 , Guohong Hu 7 , Yi Wang 5 , Yi Li 6 , Geng Chen 1 , Stefan Siwko 8 , Alison Gartland 9 , Ning Wang 9 , Jianru Xiao 4 , Mingyao Liu 1 , Jian Luo 1, 3
Affiliation
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.
中文翻译:
RSPO2 和 RANKL 信号通过 LGR4 调节破骨细胞转移前生态位形成和骨转移
针对破骨细胞的治疗是骨转移的常用治疗方法;然而,破骨细胞是否以及如何调节转移前生态位和骨趋向性在很大程度上是未知的。在这项研究中,我们报告破骨细胞前体 (OPs) 可以作为转移前生态位成分,在早期阶段促进乳腺癌 (BCa) 骨转移。在分子水平上,BCa 细胞中的无偏 GPCR 配体/激动剂筛选表明,R-spondin 2 (RSPO2) 和 RANKL 通过与其受体 LGR4 相互作用,促进破骨细胞转移前生态位的形成并增强 BCa 骨转移。这是通过 RSPO2/RANKL-LGR4 信号通过 G α q和β调节 WNT 抑制剂 DKK1 来实现的-连环蛋白信号。DKK1 通过抑制其受体 LDL 受体相关蛋白 5 (LRP5) 而不是 LRP6 直接促进 OP 募集,通过抑制经典 WNT 信号传导上调Rnasek表达。在临床样本中,RSPO2、LGR4和DKK1的表达与BCa骨转移呈正相关。此外,可溶性 LGR4 细胞外结构域 (ECD) 蛋白作为 RSPO2 和 RANKL 的诱饵受体,可显着减轻小鼠骨转移模型中的骨转移和溶骨性病变。这些发现为 OPs 作为 BCa 骨转移转移前生态位的关键组成部分的功能作用提供了独特的见解,并将 RSPO2/RANKL-LGR4 信号转导确定为抑制 BCa 骨转移的有希望的靶标。
更新日期:2022-01-19
中文翻译:
RSPO2 和 RANKL 信号通过 LGR4 调节破骨细胞转移前生态位形成和骨转移
针对破骨细胞的治疗是骨转移的常用治疗方法;然而,破骨细胞是否以及如何调节转移前生态位和骨趋向性在很大程度上是未知的。在这项研究中,我们报告破骨细胞前体 (OPs) 可以作为转移前生态位成分,在早期阶段促进乳腺癌 (BCa) 骨转移。在分子水平上,BCa 细胞中的无偏 GPCR 配体/激动剂筛选表明,R-spondin 2 (RSPO2) 和 RANKL 通过与其受体 LGR4 相互作用,促进破骨细胞转移前生态位的形成并增强 BCa 骨转移。这是通过 RSPO2/RANKL-LGR4 信号通过 G α q和β调节 WNT 抑制剂 DKK1 来实现的-连环蛋白信号。DKK1 通过抑制其受体 LDL 受体相关蛋白 5 (LRP5) 而不是 LRP6 直接促进 OP 募集,通过抑制经典 WNT 信号传导上调Rnasek表达。在临床样本中,RSPO2、LGR4和DKK1的表达与BCa骨转移呈正相关。此外,可溶性 LGR4 细胞外结构域 (ECD) 蛋白作为 RSPO2 和 RANKL 的诱饵受体,可显着减轻小鼠骨转移模型中的骨转移和溶骨性病变。这些发现为 OPs 作为 BCa 骨转移转移前生态位的关键组成部分的功能作用提供了独特的见解,并将 RSPO2/RANKL-LGR4 信号转导确定为抑制 BCa 骨转移的有希望的靶标。