Recent work by this applicant has suggested that cell migration rates increase as tumors progress toward the metastatic phenotype. He has explored the correlation between cell migration and the metastatic phenotype by measuring the movements of normal cells and of poorly metastatic and highly metastatic tumor cells. It was found that certain molecules previously known to influence metastasis profoundly influence cell motility and we have found that members of families of actin-binding and cytoskeletal proteins known to affect cell motility also modulate metastatic potential. On the basis of his work and work by others, he proposes that increased cell motility is a central component of the metastatic phenotype that can profoundly alter metastatic potential. Over the past three years, he has studied the regulatory pathways that mediate chemotactic responsiveness in normal fibroblasts and epithelial cells. He now plans to investigate the regulation of cell motility in metastatic tumor cells.
The specific aims are as follows: 1) To determine patterns of basal and stimulated cell motility in normal cells, in poorly metastatic tumor cells, and in highly metastatic tumor cells. These will be analyzed for their rates of basal cell movement, stimulated random cell movement and directional cell movement in assays that measure basal motility, chemokinesis, chemotaxis and haptotaxis; 2. To determine the molecular mechanisms which increase motility in metastatic tumor cells. He will focus on cytoskeletal elements that regulate actin polymerization and focal adhesion assembly and on intracellular signaling pathways that he has found to direct cell motility; 3. To investigate the mechanisms by which the nm23 metastasis suppressor inhibits chemotaxis. The recent work suggests the nm23 interferes with chemotactic signaling pathways downstream of tyrosine kinase receptors. In this aim he will determine the identity of the regulatory elements that are directly or indirectly modulated by nm23; 4. To study the properties of a novel member of the beta-thymosin family that he has found up regulated in metastatic prostatic carcinoma cells. He will determine the function of the molecule in terms of actin-binding ability to influence cytoskeletal architecture, ability to influence cell motility, and ability to influence experimental tumor metastasis.
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