PDF(Pubmed)
Abstract：
Ewing sarcoma is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis. Ewing sarcoma tumors are driven by the fusion gene EWS/Fli1, and while these tumors are genetically homogenous, the transcriptional heterogeneity can lead to a variety of cellular processes including metastasis. In this study, we demonstrate that in Ewing sarcoma cells, the canonical Wnt/β-Catenin signaling pathway is heterogeneously activated in vitro and in vivo, correlating with hypoxia and EWS/Fli1 activity. Ewing sarcoma cells predominantly express β-Catenin on the cell membrane bound to CDH11, which can respond to exogenous Wnt ligands leading to the immediate activation of Wnt/β-Catenin signaling within a tumor. Knockdown of CDH11 leads to delayed and decreased response to exogenous Wnt ligand stimulation, and ultimately decreased metastatic propensity. Our findings strongly indicate that CDH11 is a key component of regulating Wnt//β-Catenin signaling heterogeneity within Ewing sarcoma tumors, and is a promising molecular target to alter Wnt//β-Catenin signaling in Ewing sarcoma patients.
摘要：
尤因肉瘤是儿童第二常见的骨癌，而在诊断时出现转移性疾病的患者预后不佳。尤文肉瘤肿瘤是由融合基因EWS/Fli1驱动的，虽然这些肿瘤是遗传同质的，转录异质性可导致包括转移在内的多种细胞过程。在这项研究中,我们证明在尤文肉瘤细胞中，经典的Wnt/β-Catenin信号通路在体外和体内都是异质激活的，与缺氧和EWS/Fli1活性相关。尤文肉瘤细胞主要在与CDH11结合的细胞膜上表达β-连环蛋白,其可以响应于外源性Wnt配体,导致肿瘤内Wnt/β-连环蛋白信号传导的立即激活。CDH11的敲低导致对外源性Wnt配体刺激的反应延迟和降低,并最终降低转移倾向。我们的发现强烈表明CDH11是调节尤文肉瘤肿瘤内Wnt//β-Catenin信号异质性的关键成分。并且是改变尤文肉瘤患者中Wnt//β-Catenin信号传导的有希望的分子靶标。
