中国科学院上海营养与健康研究所胡国宏等研究人员合作发现，SCUBE2通过调节免疫抑制性成骨细胞微环境来介导管腔型乳腺癌的骨转移。相关论文于2023年5月4日在线发表在《细胞研究》杂志上。

研究人员表明，一种雌激素受体（ER）调节的分泌蛋白SCUBE2有助于管腔型乳腺癌的骨倾向性。单细胞RNA测序分析显示，SCUBE2在早期骨转移微环境中富集了成骨细胞。SCUBE2促进了肿瘤膜锚定的SHH的释放来激活间质干细胞的Hedgehog信号，从而促进成骨细胞分化。成骨细胞沉积胶原蛋白，通过抑制性的LAIR1信号来抑制NK细胞，促进肿瘤定植。SCUBE2的表达和分泌与人类肿瘤的成骨细胞分化和骨转移有关。用Sonidegib靶向Hedgehog信号以及用中和抗体靶向SCUBE2都能有效抑制多种转移模型中的骨转移。

总的来说，这项发现为管腔型乳腺癌转移中的骨质偏好提供了机制上的解释，也为转移治疗提供了新的方法。

据悉，ER阳性的管腔型乳腺癌是一个亚型，通常转移到大多数远处器官的风险较低。然而，骨复发优先发生在管腔型乳腺癌。这种亚型特异性器官转移的机制仍然难以捉摸。

附：英文原文

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

Author: Wu, Qiuyao, Tian, Pu, He, Dasa, Jia, Zhenchang, He, Yunfei, Luo, Wenqian, Lv, Xianzhe, Wang, Yuan, Zhang, Peiyuan, Liang, Yajun, Zhao, Wenjin, Qin, Jun, Su, Peng, Jiang, Yi-Zhou, Shao, Zhi-Ming, Yang, Qifeng, Hu, Guohong

Issue&Volume: 2023-05-04

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.

DOI: 10.1038/s41422-023-00810-6

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