Preventing tumor cells from acquiring metastatic properties would significantly reduce cancer mortality. However, due to the complex nature of this process, it remains one of the most poorly understood and untreatable aspects of cancer. Ischemia and hypoxia in solid tumors are requisite in metastasis formation -- conditions that arise far from functional blood vessels and deep within tumor tissues. These secluded locations impede the observation of pre-metastatic tumor cells and their interactions with stromal cells, which are also critical in the initiation of this process. Thus, the initiation of metastasis has been incredibly difficult to model in the lab and to observe in vivo. We present an ex vivo model of the tumor microenvironment, called 3MIC, which overcomes these experimental challenges and enables the observation of ischemic tumor cells in their native 3D context with high spatial and temporal resolutions. The 3MIC recreates ischemic conditions in the tumor microenvironment and facilitates the co-culture of different cell types. Using live microscopy, we showed that ischemia, but not hypoxia alone, increases the motility and invasive properties of cells derived from primary tumors. These changes are phenotypic and can occur without clonal selection. We directly observed how interactions with stromal cells such as macrophages increased tumor invasion in conjunction with the effects of an ischemic microenvironment. Finally, we tested the effects of chemotherapy drugs under different metabolic microenvironments and found that ischemic tumor cells are more resistant to paclitaxel, possibly due to a metabolic resistance mechanism. Overall, the 3MIC is a cost-effective system that allows for the dissection of the complexity of the tumor microenvironment and direct observation of the emergence of metastasis, as well as the testing of treatments that may halt this process.