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

Cell Research volume 33, pages 464–478 (2023)Cite this article

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Abstract

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.

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Fig. 1: SCUBE2 correlates with bone metastasis and is regulated by ER signaling in luminal breast cancer.
Fig. 2: SCUBE2 promotes bone metastasis of breast cancer.
Fig. 3: scRNA-seq analysis identified osteoblast enrichment in bone niches of SCUBE2-expressing tumor cells.
Fig. 4: SCUBE2 promotes osteogenic niche formation by releasing tumoral SHH.
Fig. 5: SCUBE2 promotes bone metastasis by activating Hedgehog signaling in pre-osteoblasts.
Fig. 6: Osteoblasts promote tumor survival by immune suppression.
Fig. 7: The collagen-LAIR1 axis mediates osteoblast-induced immune suppression.
Fig. 8: Clinical relevance and therapeutic targeting of Hedgehog signaling and SCUBE2 in bone metastasis.

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Data availability

The sequence data of osteoblasts were deposited in the National Omics Data Encyclopedia (NODE) with the primary accession number OEP002689. Original data of all figures were deposited in Mendeley Data (https://data.mendeley.com/v1/datasets/jkpn67jwsd/draft?preview=1). Other data of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Kai Wang, Shuyang Yan, Xiang Miao, Yiting Yuan, Jun Li, Zhonghui Weng, Yujia Zhai, Yifan Bu from Institutional Center for Shared Technologies and Facilities of SINH, CAS for technical assistance. The study was funded by the National Natural Science Foundation of China (82230096, 82003090), the National Key R&D Program of China (2020YFA0112300), the Science and Technology Commission of Shanghai Municipality (19JC1416100) and the Youth Innovation Promotion Association of Chinese Academy of Sciences.

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Authors and Affiliations

  1. Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Yunfei He, Wenqian Luo, Xianzhe Lv, Yuan Wang, Peiyuan Zhang, Yajun Liang, Jun Qin & Guohong Hu

  2. Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    Wenjin Zhao

  3. Department of Pathology, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    Peng Su

  4. Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China

    Yi-Zhou Jiang & Zhi-Ming Shao

  5. Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, China

    Qifeng Yang

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Contributions

G.H. supervised this work. Q.W. and G.H. drafted the manuscript. Q.W., P.T., D.H., Z.J., Y.H., W.L., X.L., Y.W., P.Z. and Y.L. performed the experiments. W.Z., P.S., J.Q., Y.-Z.J., Z.-M.S. and Q.Y. contributed to clinical sample collection and analyses. All authors discussed the results and commented on the manuscript.

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Correspondence to Qifeng Yang or Guohong Hu.

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Wu, Q., Tian, P., He, D. et al. SCUBE2 mediates bone metastasis of luminal breast cancer by modulating immune-suppressive osteoblastic niches. Cell Res 33, 464–478 (2023). https://doi.org/10.1038/s41422-023-00810-6

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