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SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches

Qiuyao Wu1 , Pu Tian1 , Dasa He1 , Zhenchang Jia1 , Yunfei He1 , Wenqian Luo1 , Xianzhe Lv1 , Yuan Wang1 , Peiyuan Zhang1 , Yajun Liang1 , Wenjin Zhao2 , Jun Qin1 , Peng Su3 , Yi-Zhou Jiang4 , Zhi-Ming Shao4 , Qifeng Yang5,* , Guohong Hu1,*

1Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
2Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
3Department of Pathology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
4Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China
5Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, China
* Correspondence: Qifeng Yang(qifengy@163.com)Guohong Hu(ghhu@sinh.ac.cn)

Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment.

https://www.nature.com/articles/s41422-023-00810-6

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