A traditional view of metastasis is that it results from a process similar to Darwinian evolution involving the natural selection of tumor cells that are capable of migration and survival during treatment and at distant sites. In this model the selection of tumor cells exhibiting stable genetic changes occurs, the selected cells are very rare, local and cause metastasis late in tumor progression. The recent development of new technologies, including high-density microarray based expression profiling, multiphoton intravital imaging and the collection and characterization of migratory tumor cells from live tumors and bone marrow disseminated tumor cells (DTCs) from patients, have challenged this traditional model of metastasis. The new technologies indicate that metastatic ability is acquired at much earlier stages of tumor progression than predicted by the Darwinian model, is encoded throughout the bulk of the primary tumor, it is highly plastic and involves transient changes in gene expression. These results have led to the micro-environment model of metastasis. The micro-environment and Darwinian models can be reconciled if tumor progression resulting from the selection of stable genetic changes in the primary tumor during progression, contributes the micro-environments necessary to induce the transient changes in gene expression that support the invasive and metastatic phenotype. That is, the tumor micro-environment initiates the transient epigenetic expression of genes that induce tumor cell migration, survival and metastasis. Examples of such micro-environments in breast tumors are extracellular matrix density, inflammation, and hypoxia. To study these micro-environments and their effects on metastatic phenotype, we have assembled a multidisciplinary team who will collaborate using their special expertise to: 1. fate map tumor cells to determine if tumor cells migrating from different spontaneous, and nano-device generated soluble factor-derived micro-environments, have different migration, dissemination, dormancy and growth patterns in target organs. 2. Determine the spatial and temporal extent and functional consequences of these micro-environments at single cell resolution in vivo in primary tumors and in DTCs 3. Isolate and characterize the metabolomics, genomics and epigenomics of special populations of tumor cells such as the migratory and dormant tumor cells in disseminated locations. 4. Investigate ECM-dependent migratory/invasive, dormant and proliferative tumor cell phenotypes. 5. Extend key observations to human breast and head and neck squamous tumors.