Role of GATA2 signaling network in Lethal Prostate Cancer

项目总结 尽管最近在治疗晚期前列腺癌方面取得了进展，但这种恶性肿瘤仍然是一种致命的疾病。 主要是由于前列腺癌细胞在标准治疗中存活的能力，并进展到高度 好斗的状态。因此，临床上有必要为晚期前列腺癌寻找新的分子靶点。 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，通过发展对分子靶标的机械理解来发现分子靶标 调节GATA2在致命性前列腺癌中实施和表征新的治疗方法。以下项目需要GATA2 通过作为主要调节基因作用增强前列腺癌细胞的成瘤性并存活 控制复杂的信号网络，包括对已建立的癌基因(FOXM1， IGF2、PAK4)和肿瘤抑制因子下调(GLANT7、ARRDC3)。值得注意的是，GATA2水平是 最高的是已经进展到标准的抗雄激素和化疗药物的患者。因此， 解剖GATA2信号网络可能是确定新的治疗靶点的一个有价值的策略。 为了确定临床相关的GATA2依赖的前列腺癌侵袭性机制，我们 询问了GATA2基因敲除化疗耐药前列腺癌的基因表达谱 体外模型系统和公共可用的前列腺癌组织样本基因表达数据集。其中 鉴定出的分子是跨膜核孔蛋白POM121。我们假设GATA2促进 调节核孔复合体的化学计量比和增加前列腺癌的侵袭性 特定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 首先，我们将阐明GATA2调节核孔组成和 通过POM121导入核质。在第二个目标中，我们将描述分子致癌 POM121调节前列腺癌侵袭性的效应物和机制。在第三个目标中， 我们将在转移性前列腺癌的循环肿瘤细胞中研究这些发现的临床相关性。 肿瘤患者治疗前后进展及靶向治疗的体内疗效 治疗前列腺癌的核质进口设备。

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.