Modeling the Complexity of the Metastatic Niche Ex Vivo

Cancer mortality predominantly results from distant metastases that are undetectable at diagnosis and escape initial therapies to lie as dormant micrometastases for years. To study the behavior of micrometastases-how they resist initial treatments and then awaken from a dormant state-we utilize the Legacy LiverChip^®, an all-human ex vivo hepatic microphysiological system. The functional liver bioreactor, comprising hepatocytes and non-parenchymal cells in a 3D microperfused culture format, mimics the dormant-emergent metastatic progression observed in human patients: (a) a subpopulation of cancer cells spontaneously enter dormancy, (b) cycling cells are eliminated by standard chemotherapies, while quiescent dormant cells remain, and (c) chemoresistant dormant cells can be stimulated to emerge. The system effluent and tissue can be queried for proteomic and genomic data, immunofluorescent imaging as well as drug efficacy and metabolism. This microphysiological system continues to provide critical insights into the biology of dormant and re-emergent micrometastases and serves as an accessible tool to identify new therapeutic strategies targeting the various stages of metastasis, while concurrently evaluating antineoplastic agent efficacy for metastasis, metabolism, and dose-limiting toxicity.