(verbatim): Now that numerous important genes associated with tumor angiogenesis, invasion, and metastasis have been discovered, the grand challenge is to understand their function in intact animals. The second major challenge is to integrate and apply this knowledge to cancer prevention, detection and treatment. In the proposed BRPG, we will meet these challenges with a new, more precise, quantitative, integrative, and multi-disciplinary bioengineering approach. This new bioengineering approach builds on unique and innovative techniques such as 1) genetically engineered mice to visualize gene expression, 2) in vivo models to visualize molecular and cellular events, 3) computer-assisted in vivo microscopy to quantify gene expression and function continuously and non-invasively at high (1-10pm) resolution in intact animals, 4) mathematical modeling to integrate the resulting information. Using this powerful technology, we will investigate four critical aspects of tumor metastasis: angiogenesis, invasion, hematogenous metastasis and lymphangiogenesis lymphatic metastasis. In the first year we will achieve several significant milestones: i) critically test the longstanding but unproven hypothesis that angiogenesis litates metastasis by increasing cell shedding; ii) establish a quantitative link between cell traction force and invasion through the tissue matrix; iii) demonstrate that stress generated by proliferating cancer cells can collapse lymphatic vessels in tumors; iv) provide the quantitative relationship between nitric oxide (NO) and angiogenesis in vivo. In the second and third years we will build on these findings to provide deeper quantitative insight into expression and function of three genes (NO synthase, VEGF-A, VEGF-C) considered critical to these four aspects of metastasis. Years four and five will see integration of these data in a unified framework and identification of strategies for clinical translation. The proposed BRPG offers a new paradigm for integrative studies of the dynamics of gene expression and function in cancer. With this new paradigm available to our collaborating partners working at the forefront of genomics and proteonomics, this BRPG will facilitate translation of knowledge about the molecular biology of cancer into effective cancer prevention, detection, and treatment strategies.
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