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Metastasis is a major clinical challenge driven by poorly understood cell state alterations. The goal of our lab is to use unbiased genomic methods and in vivo models to better understanding the molecular and cellular changes that underlie tumor progression and each step of the metastatic cascade. We use genetically-engineered mouse models of metastatic cancer in which the resulting tumors recapitulate the genetic alterations and histological progression of the human disease.In these models, tumors develop within their appropriate microenvironment and undergo changes in their gene expression programs that endow them with the ability to invade blood and lymphatic vessels, survive in circulation, enter various distant organs, and ultimately grow into new tumor lesions. Given the dearth of human tissue samples from metastatic disease, especially from primary tumors and metastases from the same patient prior to therapy, these models represent a unique opportunity to understand the molecular biography of the most prevalent tumor types.By generating activating and inactivating germline and inducible alleles, and modulating gene expression using lentiviral vectors, these models allow us to characterize the function of candidate genes and pathways during tumor progression and metastasis in vivo. By incorporating increasingly quantitative methods and powerful in vivo methods, our work is focused on uncovering general rules that govern tumor progression and metastatic spread and discovering novel therapeutic targets across the continuum of cancer progression including the lethal metastatic stage.