Mechanical stress reprograms mitochondrial metabolism to support tumor survival and invasion through the mitochondrial unfolded protein response

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Project Summary Aberrant metabolic and physical characteristics are the most salient features of tumors when compared to their tissue of origin. My proposed research program will molecularly define how mechanical stresses alter mitochondrial metabolism to support metastatic disease. My preliminary data show that genetic and exogenous mechanical stress can metabolically reprogram mammary epithelial cells by inducing the mitochondrial unfolded protein response (UPRmt) which induces adaptations known to be enriched in metastatic tumors. Clarifying the relationship between cellular mechanics, mitochondrial signals, and adaptive stress responses may uncover unforeseen cancer treatment opportunities while also explaining the interconnectedness of the mechanical and metabolic abnormalities of cancerous tissues. I will use simplified two dimensional ECM functionalized polyacrylamide hydrogels (PA-gels) that recapitulate the “normal” tissue stroma (400 Pa), the premalignant and early invasive promoting stroma (6 kPa), and the highly rigid tumor stroma (60 kPa) to assess the impact of ECM stiffness on mitochondrial metabolism, redox signaling, and cancer associated adaptive stress responses (UPRmt mediated by HSF1 and ATF5). In these models of mechanical stress, I will define the roles of HSF1 and ATF5, mitochondrial structural transitions, integrin signal transduction (via genetic and pharmacological approaches), and actomyosin mediated contractility (via genetic and pharmacological approaches). I will then interrogate if the cellular responses to mechanical signals of the tumor microenvironment require HSF1 and ATF5 to dispose malignant behavior using mammary tumor models developed in the Weaver lab. In summary, Aim 1: Characterize the mitochondrial changes that occur in response to mechanical stress. Aim 2: Determine if mitochondrial reactive oxygen signals trigger adaptive stress responses and metastatic cytoskeletal dynamics. Aim 3: Test if viability and invasiveness of mammary tumors catalyzed by mechanical stresses is disposed through an HSF1- and ATF5-mediated UPRmt induced by mitochondrial oxidant signals. Additionally, to accomplish this project I will learn and use experimental techniques and concepts that my mentors and I have identified as important experiential training opportunities that will engender my independent research career.