The goal of our studies is to develop a quantitative understanding of tumor metastasis. As cell migrationis the central part of metastasis, we are developing quantitative experimental and computational methods tostudy migration in three dimensional matrices. Our preliminary studies have indicated that cancer cell migrationin two and three dimensional matrices is significantly different. The effects of matrix structure and mechanicsas well as extracellular degradation by proteolytic enzymes can not be studied in existing two dimensionalassays. This lack of information about key processes and variables leads to incomplete and inaccurateunderstanding. Our goal is to rectify these problems by quantifying tumor cell migration in native like threedimensional environments.In the proposed studies, we will develop a system level understanding of tumor cell migration. The individualand collective roles of cell adhesion, matrix composition, matrix structure and proteolysis will be studied in wellestablished prostate cancer cell lines. This will be accomplished through the following specific aims: 1)Quantify the systematic interactions of integrins and extracellular matrix in regulating three -dimensional tumorcell motility, 2) Quantify the effects of extracellular matrix structure on protease activity in tumor cells and 3)Develop multi-scale computational models to predict and quantify cell adhesion and migration in threedimensional matrices.Our ability to combat and cure cancer rests on our understanding of the processes regulating metastasis. Theproject outlined in this proposal will be a significant step in reaching that level of understanding. By combiningexperiments and simulations, carried out in controlled environments that mimic in vivo settings, we will be ableto quantify the individual and collective roles of matrix and cells in tumor cell migration. The systems levelquantification achieved through our experiments and simulation will serve as a platform for discovery of anti-cancer therapeutics. The main reason for cancer related deaths is the progression of cancer from a localized tumor to the vital organsof the body, a process otherwise known as metastasis. Thus our ability to combat and cure cancer rests on ourunderstanding of the processes regulating metastasis. The project outlined in this proposal will be a significantstep in reaching that level of understanding.
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