The histone demethylase KDM3A upregulates MCAM to promote Ewing Sarcoma metastasis

 描述（由申请人提供）：本提案的长期目标是确定尤文肉瘤可能的新治疗靶点。一旦患者发生远处转移，他/她的5年生存率就会降至30%。此外，在70%最初接受局部疾病治疗的患者中，30%将在最初缓解后几年内在转移部位复发。由于尤文肉瘤是一种具有强烈早期扩散倾向的侵袭性疾病，因此特别需要能够潜在地预防肿瘤扩散的新疗法。我们的实验室已经确定了一个表观遗传修饰剂，KDM 3A，作为尤文肉瘤迁移和体内转移的正调控因子。进一步的分析表明，KDM 3A对许多促进转移的基因具有调节能力，包括黑素瘤细胞粘附分子（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迁移。重要的是，MCAM最近被确定为在许多不同类型的儿科肿瘤中过表达，包括尤文肉瘤。我们自己的初步数据与其他模型的已发表工作相结合，导致我们的假设，KDM 3A促进尤文肉瘤的生长和传播，通过上调MCAM。以下具体目标将检验这一假设。具体目标1.确定MCAM在体外尤文肉瘤中KDM 3A诱导的转移表型中的作用和机制。具体目标2。确定KDM 3A、MCAM和FAK抑制对尤文肉瘤体内转移的相对作用。了解KDM 3A及其下游靶点MCAM如何促进转移，可能有助于我们确定尤文肉瘤的新治疗方法。

 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.