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.
Our studies will validate the role of the cancer nodal genes Hsp90s in the regulation of mitochondrial bioenergetics and metastatic disease. We anticipate learning novel fundamental concepts that should directly impact on our understanding of the molecular basis of the metastatic disease and therefore impact on the development of novel therapeutic avenues. Therefore the relevance of our work for public health resides in the possibility of identifying novel therapeutic targets to prevent the metastatic dissemination of cancer.