ECM Stiffness as a Regulator of Tumor Cell Dissemination and Dormancy

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We hypothesize that dense collagen matrices create a mechanical "stress" environment that alters cellular invasion and cellular metabolism, and promotes, depending on the ECM composition, proliferation or dormancy at metastatic target sites. We propose that changes in the fluorescence lifetime of NAD(P)H and FAD can be used 1) in the research setting to track and understand disease progression, macrophage infiltration, disseminated tumor cells (DTCs) and dormancy; and 2) developed for use in the clinical setting to provide early information about tumor progression and dissemination. NAD(P)H and FAD are particularly attractive potential biomarkers for clinical use, as they are endogenous signals that require no external label and can be imaged in fresh or fixed biopsy samples. These questions will be addressed in three specific aims: 1) Determine whether local regions of increased stress (mechanical, hypoxic or hypoglycemic) alter the metabolic signature of tumor and stromal cells; 2) Investigate mechanisms by which fibrosis affects the dormancy and metabolic signatures of DTCs ;3) Determine whether metabolic and dormancy signatures are useful predictors of stage and outcome in human HNSCC and breast cancer patients.