Gyau Benjamin B, Wang Junyan, Chen Xiang, Clement Margaret A, Man Zoe D, Major Angela M, Weiser Mathew C, Xu Jun, Hicks John, Man Tsz-Kwong
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Cancer and Hematology Center, Houston, TX, USA.
J Bone Oncol. 2025 May 23;52:100690. doi: 10.1016/j.jbo.2025.100690. eCollection 2025 Jun.
The CXCL10-CXCR3 axis regulates immunity, tumorigenesis, and metastasis in multiple cancers. Yet, its roles in osteosarcoma (OS), the predominant pediatric malignant bone tumor, are not fully defined. Our prior work has shown that elevated serum CXCL10 levels correlate with poor OS prognosis. The current study delves deeper by investigating how CXCL10-mediated CXCR3 signaling influences OS growth and metastatic spread. , CXCL10 and related CXCR3 ligands (CXCL4, CXCL9, and CXCL11) enhanced OS tumor cell migration. In an orthotopic xenograft mouse model with a newly created CXCR3 knockout (KO) mutant, tumor growth and lung metastasis decreased significantly when compared with the parental cell line. Transfecting the transcript isoform CXCR3A, but not CXCR3B, into KO cells restored metastatic phenotypes in mice, highlighting isoform specificity. Pharmacological CXCR3 inhibition reduced OS cell migration and metastasis . Mechanistically, CXCL10 triggered AKT (S473) and PAK1 (S144) phosphorylation in OS cell lines, but not in the KO mutant, implicating the role of these kinases in CXCL10-mediated metastasis. Collectively, our data indicate the CXCL10-CXCR3 axis as a key metastatic driver in OS, suggesting CXCR3 as a viable therapeutic target for treating OS metastasis.
CXCL10-CXCR3轴在多种癌症中调节免疫、肿瘤发生和转移。然而，其在骨肉瘤（OS）（一种主要的儿童恶性骨肿瘤）中的作用尚未完全明确。我们之前的研究表明，血清CXCL10水平升高与骨肉瘤预后不良相关。当前的研究通过调查CXCL10介导的CXCR3信号如何影响骨肉瘤的生长和转移扩散进行了更深入的探究。CXCL10和相关的CXCR3配体（CXCL4、CXCL9和CXCL11）增强了骨肉瘤肿瘤细胞的迁移。在一个新创建的CXCR3基因敲除（KO）突变体的原位异种移植小鼠模型中，与亲代细胞系相比，肿瘤生长和肺转移显著减少。将转录异构体CXCR3A而非CXCR3B转染到基因敲除细胞中可恢复小鼠的转移表型，突出了异构体特异性。药理学上的CXCR3抑制减少了骨肉瘤细胞的迁移和转移。从机制上讲，CXCL10在骨肉瘤细胞系中触发了AKT（S473）和PAK1（S144）的磷酸化，但在基因敲除突变体中未触发，这表明这些激酶在CXCL10介导的转移中发挥了作用。总体而言，我们的数据表明CXCL10-CXCR3轴是骨肉瘤中关键的转移驱动因素，提示CXCR3是治疗骨肉瘤转移的一个可行治疗靶点。
