The histone demethylase KDM3A upregulates MCAM to promote Ewing Sarcoma metastasis

 描述(由申请人提供)：这项提案的长期目标是确定尤因肉瘤可能的新治疗靶点。一旦患者转移到远处，他/她的5年生存率下降到30%。此外，在最初接受局部治疗的70%的患者中，30%的患者在最初缓解的几年内会在转移部位复发。由于尤因肉瘤是一种侵袭性很强的疾病，有很强的早期扩散倾向，因此特别需要有可能防止肿瘤扩散的新疗法。我们的实验室已经确定了一种表观遗传学修饰物KDM3A，它是尤文肉瘤转移和体内转移的积极调节因子。进一步的分析表明，KDM3A对一些促进转移的基因具有调节力，包括黑色素瘤细胞黏附分子(MCAM)。MCAM在其他几种类型的癌症中过表达，我们已经证明它可以促进肿瘤细胞的迁移。重要的是，MCAM最近被发现在包括尤因肉瘤在内的许多不同类型的儿科肿瘤中过表达。我们自己的初步数据与其他模型发表的工作相结合，得出了我们的假设，即KDM3A通过上调MCAM促进尤文肉瘤的生长和扩散。以下具体目标将检验这一假设。具体目的1.确定MCAM在KDM3A诱导尤文肉瘤体外转移表型中的作用及机制。具体目的2.检测KDM3A、MCAM和FAK对尤文肉瘤体内转移的抑制作用。了解KDM3A及其下游靶分子MCAM是如何促进转移的，可能有助于我们找到治疗尤因肉瘤的新方法。

 DESCRIPTION (provided by applicant): The long term goal of this proposal is to identify possible new therapeutic targets for Ewing Sarcoma. Once a patient develops metastasis to distant sites, his/her 5-year survival drops to 30%. Moreover, of the 70% of patients treated with initially localized disease, 30% will relapse at metastatic sites within a few years of initial remission. As Ewing Sarcoma is such an aggressive disease with strong propensity for early spread, new therapies that could potentially prevent tumor spread are in particular need. Our laboratory has identified an epigenetic modifier, KDM3A, as a positive regulator of Ewing Sarcoma migration and in vivo metastasis. Further analysis has shown that KDM3A holds regulatory power over a number of genes which promote metastasis, including Melanoma Cell Adhesion Molecule (MCAM). MCAM is overexpressed in several other types of cancers, and we have shown it to promote tumor cell migration. Importantly, MCAM has recently been identified as overexpressed in many different kinds of pediatric tumors, including Ewing Sarcoma. Our own preliminary data in conjunction with published work from other models lead to our hypothesis that KDM3A promotes Ewing sarcoma growth and dissemination through upregulation of MCAM. The following specific aims will test this hypothesis. Specific aim 1. Determine the role and mechanism of MCAM in KDM3A- induced metastatic phenotypes in Ewing Sarcoma in vitro. Specific aim 2. Determine the relative effects of KDM3A, MCAM and FAK inhibition on Ewing sarcoma metastasis in vivo. Understanding how KDM3A and its downstream target MCAM function to promote metastasis, may help us identify new therapeutic approaches for Ewing Sarcoma.