Mitochondrial Hsp90s Regulation of Tumor Bioenergetics and Metastasis

描述（由申请人提供）：细胞应激感应途径有助于适应不利的肿瘤微环境条件（如营养剥夺、酸中毒和缺氧）和获得新的恶性特性。在这种情况下，Hsp90家族的分子伴侣是结节癌基因，控制参与肿瘤细胞增殖、生存和应激适应的客户蛋白的折叠和成熟。Hsp90线粒体池（mtHsp90）及其相关伴侣蛋白TRAP-1在肿瘤细胞中拮抗线粒体通透性转变并维持能量产生。我们小组最近的证据表明，mthsp90导向的生物能量学对于拮抗巨噬和调节细胞器未折叠蛋白反应（UPR）至关重要，UPR导致肿瘤细胞基因表达的深度代偿性重构。自加入Altieri实验室以来，我发现用一种选择性地在线粒体中积累的小分子抑制剂（Gamitrinib）靶向Hsp90s的伴侣atp酶活性，抑制细胞运动激酶FAK和Src的激活，抑制细胞骨架动力学，抑制肿瘤细胞的迁移和侵袭。我们假设线粒体hsp90是肿瘤转移的新调节因子。在本研究中，我们将研究自噬和UPR对线粒体hsp90调控肿瘤细胞骨架动力学和运动的作用，以及它们对体内转移传播的贡献。在Aim 1中，我们提出阐明mtHsp90s调节自噬启动复合物在代谢应激下FAK激活和肿瘤细胞运动中的分子要求。在Aim 2中，我们将研究UPR在mthsp90介导的肿瘤细胞骨架动力学调节中的作用。在Aim 3中，我们将验证mthsp90在体内转移动物模型中的作用。我们的研究将验证线粒体hsp90调控肿瘤生物能量学对转移性疾病的重要性，长期目标是确定新的治疗靶点，以防止癌症的转移传播。这里提出的研究计划将在多个调查领域拓宽我的知识，批判性思维和整体背景训练

DESCRIPTION (provided by applicant): Cellular stress sensing pathways contribute to adaptation to unfavorable tumor microenvironment conditions (e.g. nutrient deprivation, acidosis and hypoxia) and to the acquisition of new malignant properties. In this context, the molecular chaperones of the Hsp90 family are nodal cancer genes, controlling the folding and maturation of client proteins involved in tumor cell proliferation, survival and adaptation to stress. Mitochondrial pools of Hsp90 (mtHsp90) and its related chaperone, TRAP-1, antagonize mitochondrial permeability transition and maintain energy production in tumor cells. Recent evidences from our group indicate that mtHsp90s- directed bioenergetics is essential to antagonize macroautophagy and to regulate an organelle unfolded protein response (UPR) that leads to profound compensatory remodeling of gene expression in tumor cells. Since joining the Altieri laboratory, I found that targeting the chaperone ATPase activity of Hsp90s with a small molecule inhibitor selectively engineered to accumulate in mitochondria (Gamitrinib), suppressed activation of cell motility kinases FAK and Src, inhibited cytoskeletal dynamics and suppressed tumor cell migration and invasion. We hypothesize that mitochondrial Hsp90s are novel regulators of metastasis in tumors. In the present application we will investigate the role o autophagy and the UPR on mitochondrial Hsp90s regulation of tumor cell cytoskeletal dynamics and motility, and their contribution to metastatic dissemination in vivo. In Aim 1, we propose to elucidate the molecular requirements for mtHsp90s modulation of the autophagy initiating complex in FAK activation and tumor cell motility under metabolic stress. In Aim 2, we will study the involvement of the UPR in mtHsp90s-mediated regulation of cytoskeletal dynamics in tumor cells. In Aim 3, we will validate the role of mtHsp90s in animal models of metastasis in vivo. Our studies will verify the importance of the regulation of tumor bioenergetics by mitochondrial Hsp90s for metastatic disease, with the long term goal of identifying novel therapeutic targets to prevent the metastatic dissemination of cancer. The research plan proposed here will broaden my knowledge, critical thinking and overall background training in multiple fields of investigation including cell biology, biochemistry, molecular biology and cancer biology. I will also gain invaluable expertise in a broad range of quantitative approaches for the study of cell motility, UPR, tumor cell invasion and animals models of metastasis, in vivo. My goal for this training mechanism is to integrate all this new knowledge and formulate a comprehensive understanding of how key stress and metabolic pathways modulate metastasis. By completing the other components of my training plan I expect to become extremely competent in the planning, implementation and communication of my research results, develop a professional responsibility for conducting research, as well as learn key interpersonal skills essential to become an independent investigator. In summary, the present application is expected to support my successful establishment as a responsible and productive independent investigator.