The emergence of metastases in organs distant from the primary tumor is the most devastating aspect of cancer. The major obstacle for treatment of established metastaes could well be their biologic heterogeneity which results from the continuous evolution of tumors and is responsible for the multiple differences that exist among tumor cells of a single metastasis. To date, most of the data on the biology of metastasis have been derived from studies with rodent neoplasms. It is now necessary extend our investigations into relevant human tumor systems. My long-term goals are to understand the mechanisms that regulate the metastatic spread of human neoplasms and the development of biologic heterogeneity in order to develop new approaches to the prevention and treatment of metastasis in humans. In the coming years, I will investigate the extent of metastatic heterogeneity in freshly isolated human neoplasms. Specific patterns of metastatic spread will also be studied in relation to properties of the neoplastic cells and the nature of the host microenvironment. Metastatic and nonmetastatic subpopulations will be selected from human neoplasms and the genetic and epigenetic mechanisms involved in tumor progression and metastasis will be investigated. The biologic diversity of nepolasms implies that the successful treatment of metastasis will require the total destruction of all cancer cells. The challenge to the oncologist is, therefore, to devise a new approach for the eradication of the few tumor cells that resist conventional therapies. Such an approach would have to circumvent the problem of neoplastic heterogeneity and the emergence of treatment-resistant variant tumor cells. Studies from my laboratory and many others suggest that appropriately activated macrophages can meet these demanding criteria and, thus, provide a biological approach to the destruction of the few but fatal tumor cells that resist or escape conventional therapies. For this reason, the second major goal of my research is to study the role of the macrophage in the pathogenesis of cancer matastasis, to devise methods for systemic activation of macrophages, and to elucidate the mechanisms by which tumoricidal macrophages discriminate between tumorigenic and nontumorigenic cells.