Breast cancer mortality is driven by metastasis, a process that is initiated by local invasion into the tumor stroma towards the vasculature. Cancer invasion has been found to be mediated through various mechanisms, including the acquisition of a cancer stem-like cell (CSC) phenotype and metabolic reprogramming. Furthermore, these traits are known to be regulated by key features of the tumor microenvironment such as a dense 3D collagen-rich matrix that cancer cells must invade through and blood vessels that supply nutrients and signaling molecules. However, the functional connections between the acquisition of an invasive phenotype, metabolic reprogramming, and the role of the vasculature in these processes remain unclear. This is due in part to a lack of model systems that can recapitulate features of the tumor-vasculature stroma and integrated analysis techniques to assess cell metabolism and invasion at a spatiotemporal resolution. Thus, the goal of this doctoral research was to develop and utilize an integrated suite of modeling and analysis techniques to test the hypothesis that invasion through a 3D matrix is enabled by metabolic reprogramming and that blood vessels facilitate this process through cell signaling. The first part of this doctoral work focused on determining the role of metabolic reprogramming on the acquisition of invasive CSC properties using a convergent set of model systems, engineered cell lines, and computational modeling. Second, an in vitro vasculature model was developed to study cancer invasion into a 3D collagen matrix towards an integrated endothelial cell channel. Finally, this engineered vasculature model was utilized to investigate metabolic regulation of cancer invasion in response to endothelial cell secreted factors from a functional vessel. The results from this research suggest that CSCs overproduce hyaluronic acid which is associated with metabolic adaptations to satisfy the energy demands for 3D invasion. Additionally, ECs that make up the vasculature induce increased invasion and similar metabolic adaptations seen in CSCs. This work introduces an innovative suite of engineered model systems, computational analysis, and metabolic imaging tools to study invasion and metabolic reprogramming in a physiologically relevant context while revealing the contributions of the vasculature and metabolism to cancer metastasis.