Triple negative breast cancer (TNBC) patients present a formidable clinical challenge, as they exhibit higher rates of metastatic recurrence, and respond poorly to available targeted therapies. Given the clinical significance, it is imperative to develop effective targeted anti-metastatic therapies for the treatment of TNBC. Metals serve as co-factors for tumor promoting pathways and targeting metals to disable these pathways has emerged as a potential anti-cancer therapeutic strategy. Copper, an essential trace element functions as a catalytic cofactor for a host of metalloenzymes/proteins that contribute to tumor angiogenesis and metastasis. In addition, increased copper uptake by malignant cells has led to the development of copper-specific chelators as therapeutic agents. In a potentially transformative discovery, we have identified within the primary tumor, a discrete population of highly metastatic OCT4+ SOX2+ cells. We show that these metastatic cells have significantly elevated levels of intracellular copper and exhibit increased sensitivity to copper deficiency. We have also shown that copper depletion alters the architecture of extracellular matrix in the metastatic lungs of both mouse and human. Our central hypothesis is that copper contributes to two key aspects of metastasis: cancer cell intrinsic metabolic pathways that directly contribute to metastasis; and the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells. To test this hypothesis, we will use pre-clinical models to elucidate cellular and molecular mechanisms of oral copper chelator tetrathiomolybdate (TM) and leverage banked samples from our completed phase II TM clinical trial to develop collagen remodeling products as biomarkers of TM response. The central goal of this proposal is to understand the mechanistic basis of copper depletion as a viable treatment approach against TNBC metastasis. We expect to make significant advances through the following aims. Aim 1 will establish the direct link between copper-mediated metabolic reprograming and metastasis in TNBC and dissect key cellular and molecular mechanisms, and Aim 2 will investigate how copper deficiency reprograms the extracellular matrix in the distal metastatic organs to generate an inhospitable microenvironment to impair metastasis and develop clinically valuable biomarkers of response to TM. Fundamental discoveries from these integrated pharmacological and genetic investigations has the potential not only to advance TM into larger randomized trials, but to identify new copper pathways for the development of novel therapeutic strategies against TNBC.