He Yunfei, Yang Peng, Ding Peng, Zhang Zeng, Wu Jichuan, Wang Chunjie, Hou Guanghui, Ge Jun, Zhou Quan, Song Zhuorun, Yang Huilin, Liu Tao, Lu Shunyi
Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Institutes for Translational Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215123, China.
Theranostics. 2025 Jun 20;15(15):7454-7466. doi: 10.7150/thno.113887. eCollection 2025.
The lung is the most common site of metastasis in osteosarcoma, with pulmonary dissemination accounting for most of the disease-related mortality. Despite its clinical significance, the underlying mechanisms is poorly defined. To investigate the clinical relevance of GD2, we performed GD2 immunofluorescence staining on a cohort of human tumor samples. To explore the functional role of GD2 in lung metastasis, we employed an intravenous injection model and an intratibial injection model using U2OS and 143B cells respectively. To elucidate how GD2 regulates osteosarcoma lung metastasis, we carried out an flow-based phagocytosis assay. We identify the disialoganglioside GD2 as a key mediator of osteosarcoma lung metastasis through impairing macrophage phagocytic function. Mechanistically, GD2 interacts with SIGLECE in mice (or SIGLEC7 in humans) on the cell surface of macrophages, leading to the activation of SH2-containing protein tyrosine phosphatase 2 (SHP2), which in turn suppresses macrophage phagocytic function. Notably, co-treatment with an anti-GD2 antibody and the SHP2 inhibitor SHP099 resulted in a synergistic reduction of lung metastasis. Our findings uncover a mechanism of osteosarcoma lung metastasis and highlight the GD2-SIGLEC-SHP2 axis as a promising therapeutic target.
肺是骨肉瘤最常见的转移部位，肺转移是导致大多数与疾病相关死亡的原因。尽管其具有临床意义，但其潜在机制仍不清楚。为了研究GD2的临床相关性，我们对一组人类肿瘤样本进行了GD2免疫荧光染色。为了探究GD2在肺转移中的功能作用，我们分别使用U2OS和143B细胞建立了静脉注射模型和胫骨内注射模型。为了阐明GD2如何调节骨肉瘤肺转移，我们进行了基于流式细胞术的吞噬试验。我们发现双唾液酸神经节苷脂GD2通过损害巨噬细胞吞噬功能，成为骨肉瘤肺转移的关键介质。机制上，GD2与巨噬细胞表面的小鼠SIGLECE（或人类SIGLEC7）相互作用，导致含SH2结构域的蛋白酪氨酸磷酸酶2（SHP2）激活，进而抑制巨噬细胞吞噬功能。值得注意的是，抗GD2抗体与SHP2抑制剂SHP099联合治疗可协同减少肺转移。我们的研究结果揭示了骨肉瘤肺转移的机制，并突出了GD2-SIGLEC-SHP2轴作为一个有前景的治疗靶点。
