Modeling metastasis: engineering approaches to study the metastatic cascade

Tumor progression and metastasis requires a complex interplay between tumor cells and their surrounding environment. Conventional 2D and 3D tissue culture models lack the precision and spatiotemporal control required to accurately model the complexity of the tumor microenvironment and metastatic cascade. Advances in biomedical engineering have allowed us to generate precise and versatile model systems to elucidate mechanisms vital to tumor progression and metastasis. The incorporation of novel biomaterials creates a specific mechanical environment that has facilitated controlled studies of cancer cell mechano-transduction. In addition, microfluidic devices have not only allowed for the incorporation of flow and shear forces into vascularized tumor models, but also elucidated vital mechanisms of cancer cell migration that have shifted paradigms about the mode in which cancer cells initiate metastasis. Here, we review the latest developments in biomedical engineering approaches to model the tumor microenvironment and metastatic cascade. We discuss how these approaches have advanced the field of cancer biology and enhanced our understanding of the mechanisms driving metastasis. We initially focus on physical and mechanical aspects of the primary microenvironment that impact tumor cell invasion. We then transition to tumor cell migration using models of tumor extracellular matrix including confined migration. Finally, we review models of intravasation/extravasation and colonization of secondary sites.