Role of GATA2 signaling network in Lethal Prostate Cancer

项目摘要 尽管晚期前列腺癌的治疗最近取得了进展，但这种恶性肿瘤仍然是一种致命的疾病 这主要是由于前列腺癌细胞能够在标准治疗中存活并进展到高度恶性。 侵略性国家。因此，临床上需要确定晚期前列腺的新分子靶点。 已经发展到标准疗法的癌症。这项研究计划的主要目标是剖析 GATA2的信号网络，通过发展对GATA2的机制性理解来发现分子靶点， 调节GATA 2发挥和表征致命前列腺癌的新疗法。需要GATA2 通过作为主调节基因， 控制一个复杂的信号网络，该网络包括上调已建立的癌基因（FOXM1， IGF2、PAK4）和肿瘤抑制因子（GLANT7、ARRDC3）的下调。值得注意的是，GATA2水平 在已经进展到标准抗雄激素和化疗药物的患者中最高。因此，我们建议， 剖析GATA2信号网络可能代表了鉴定新的治疗靶点的有价值的策略。 为了确定前列腺癌细胞中临床相关的GATA 2依赖性侵袭机制，我们 研究了GATA2敲低化疗耐药前列腺癌的基因表达谱， 体外模型系统和公众可获得的前列腺癌组织样品基因表达数据集。之间 所鉴定的分子是跨膜核孔蛋白POM 121。我们假设GATA 2促进了 通过调节核孔复合物的化学计量和增加细胞核内的 特异性癌蛋白的核活性和靶向核质输入机制是一种 治疗致命前列腺癌的有效策略。我们将通过三个目标来解决这些假设。在 第一个目标，我们将阐明GATA 2调节核孔组成的机制基础， 通过POM 121的核质输入。在第二个目标中，我们将描述分子致癌性 POM 121调节前列腺癌侵袭性的效应子和机制。第三个目标， 我们将研究这些发现在转移性前列腺循环肿瘤细胞中的临床相关性。 癌症患者治疗前和治疗后的进展，沿着靶向的体内功效 用于治疗前列腺癌的核质输入机制。

PROJECT SUMMARY Despite recent progress in the treatment of advanced prostate cancer this malignancy remains a lethal disease mainly due to the ability of prostate cancer cells to survive standard therapies and progress to a highly aggressive state. Therefore, there is a clinical need to identify new molecular targets for advanced prostate cancer that have progressed to standard therapies. The main goal of this research program is to dissect the signaling network of GATA2, discover molecular targets by way of developing a mechanistic understanding of regulation GATA2 exerts and characterize novel therapies in lethal prostate cancer. GATA2 is required for survival of and to enhance the tumorigenicity of prostate cancer cells by acting as a master regulator gene that controls a complex signaling network which includes upregulation of well established oncogenes (FOXM1, IGF2, PAK4) and downregulation of tumor suppressors (GLANT7, ARRDC3). Notably, GATA2 levels are highest in patients that have progressed to standard anti-androgen and chemotherapy agents. Therefore, dissecting the GATA2 signaling network may represent a valuable strategy to identify novel therapeutic targets. To identify clinically relevant GATA2 dependent mechanisms of aggressiveness in prostate cancer cells we have interrogated the gene expression profiles of GATA2 knockdown chemotherapy resistant prostate cancer in vitro model systems and public available prostate cancer tissue sample gene expression datasets. Among the molecules identified is the transmembrane nucleoporin POM121. We hypothesize that GATA2 promotes prostate cancer aggressiveness by regulating the stoichiometry of the nuclear pore complex and increasing the nuclear activity of specific oncoproteins and that targeting the nucleocytoplasmic import machinery is an effective strategy to treat lethal prostate cancer. We will address these hypotheses through three aims. In the first aim, we will elucidate the mechanistic basis by which GATA2 regulates the nuclear pore composition and nucleocytoplasmic import through POM121. In the second aim, we will characterize the molecular oncogenic effectors and mechanisms through which POM121 regulates prostate cancer aggressiveness. In the third aim, we will investigate the clinical relevance of these findings in circulating tumor cells from metastatic prostate cancer patients before treatment and after treatment progression along with the in vivo efficacy of targeting the nucleocytoplasmic import machinery for treating prostate cancer.