Role of GATA2 signaling network in Lethal Prostate Cancer

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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.