The PPG has as its central aim the understanding of cell motility and invasion with its focus upon cellular interactions in the tumor microenvironment. These interactions can only be effectively modeled in mice and Core C provides access to mouse models of breast cancer. It allows the rapid testing (in the context of mouse breeding and genetic manipulation) of hypotheses about the importance of particular signaling molecules in the process of tumor invasion and metastasis.. The core generates genetically manipulated mice and provides access to techniques used by many investigators including, staging of mammary tumors, mammary fat pad transplantation, lung metastasis assays and intravenous injections. The PPG has pioneered the intravital imaging of different cell types within the tumor. This requires individual lineages to be marked with fluorescent proteins expressed from lineage specific promoters. To date both macrophages, endothelial and tumor cells are labeled with GFP or CFP and each of these strains are crossed with mammary tumor bearing mice. Core C maintains all these colonies and performs the multiple crosses, providing genotyping and colony maintenance services. Such large-scale mouse breeding would be impossible for any one laboratory. Furthermore, without this core, many of the members of the project program who are cell biologists and biochemists, would find it very difficult to translate their fundamental observations in cultured cells into testable hypotheses about their role in tumor progression in vivo.
The specific aims are: 1) Develop and maintain mice in which multiple cell lineages are marked by expression of fluorescent proteins. These are carried on both the MMTV-Polyoma and Her2/Neu mammary tumor-bearing mice. 2) Genetically manipulate the mouse genome in ways relevant to the PPG and develop methodology to conditionally ablate specific genes in individual cell lineages. 3) Provide assistance in tumor staging and metastasis assays. 4) Provide other techniques relevant to the PPG such as bone marrow transplantation;mammary transplantation, transgenic and gene targeting construct advice. Breast cancer is the most common cancer of women in Europe and the US causing great morbidity and mortality. Our studies have indicated an important role for the tumor microenvironment modulating metastasis. This complex interaction between cells can only be modeled in mice. Insight gained form these studies should help in the development of therapeutics that inhibit metastasis.
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