Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels, as well as an established interaction of tumor cells with their surrounding microenvironment. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer and a state of stable non-progressing disease. Micrometastasis, dormant tumors, and residual tumor cells contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that together are responsible for the vast majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly understood. We now propose to investigate the molecular and cellular changes in tumor-host interactions that govern tumor dormancy, which may lead to the discovery of novel tumor dormancy targets and provide tools for dormancy-dependent tumor therapy strategies. In order to achieve this goal, we will integrate the following basic and translational approaches: (i) Establishment of mouse models of dormant and fast-growing tumor pairs; (ii) Functional and molecular characterization of dormant versus fast-growing tumors, (iii) Design of dormancy-promoting tailor-made polymer therapeutics delivering a combination of microRNAs with chemotherapies; (iv) Polymer conjugation to a prodrug designed to be activated by specific enzymes overexpressed in tumors, Turning-ON a near infra-red (NIR) fluorescence signal.When completed, this proposal will shed light on this fundamental cancer biology phenomenon. A better understanding of tumor dormancy and the availability of markers and therapeutic targets will most likely change our perception of tumor progression and, consequently, the way we diagnose and treat the disease.