School of Medicine, Tongji University, Shanghai 200433, China; Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai 200433, China.
Cell Rep. 2024 Aug 27;43(8):114528. doi: 10.1016/j.celrep.2024.114528. Epub 2024 Jul 24.
Macrophage-to-osteoclast differentiation (osteoclastogenesis) plays an essential role in tumor osteolytic bone metastasis (BM), while its specific mechanisms remain largely uncertain in lung adenocarcinoma BM. In this study, we demonstrate that integrin-binding sialoprotein (IBSP), which is highly expressed in the cancer cells from bone metastatic and primary lesions of patients with lung adenocarcinoma, can facilitate BM and directly promote macrophage-to-osteoclast differentiation independent of RANKL/M-CSF. In vivo results further suggest that osteolytic BM in lung cancer specifically relies on IBSP-induced macrophage-to-osteoclast differentiation. Mechanistically, IBSP regulates the Rac family small GTPase 1 (Rac1)-NFAT signaling pathway and mediates the forward shift of macrophage-to-osteoclast differentiation, thereby leading to early osteolysis. Moreover, inhibition of Rac1 by EHT-1864 or azathioprine in mice models can remarkably alleviate IBSP-induced BM of lung cancer. Overall, our study suggests that tumor-secreted IBSP promotes BM by inducing macrophage-to-osteoclast differentiation, with potential as an early diagnostic maker for BM, and Rac1 can be the therapeutic target for IBSP-promoted BM in lung cancer.
巨噬细胞向破骨细胞分化（破骨细胞生成）在肿瘤溶骨性骨转移（BM）中起着至关重要的作用，而其在肺腺癌 BM 中的具体机制在很大程度上仍不清楚。在这项研究中，我们证明了整合素结合唾液蛋白（IBSP）在肺腺癌患者骨转移和原发性病变的癌细胞中高度表达，它可以促进 BM，并直接促进巨噬细胞向破骨细胞分化，而不依赖于 RANKL/M-CSF。体内结果进一步表明，肺癌的溶骨性 BM 特别依赖于 IBSP 诱导的巨噬细胞向破骨细胞分化。在机制上，IBSP 调节 Rac 家族小 GTP 酶 1（Rac1）-NFAT 信号通路，并介导巨噬细胞向破骨细胞分化的前向转移，从而导致早期溶骨。此外，在小鼠模型中，用 EHT-1864 或硫唑嘌呤抑制 Rac1 可以显著缓解 IBSP 诱导的肺癌 BM。总的来说，我们的研究表明，肿瘤分泌的 IBSP 通过诱导巨噬细胞向破骨细胞分化来促进 BM，具有作为 BM 的早期诊断标志物的潜力，而 Rac1 可以作为 IBSP 促进肺腺癌 BM 的治疗靶点。
