(69c) Capturing Microenvironmental Regulation of Metastatic Dormancy and Recurrence

Disseminated tumor cells (DTCs) undergo varying periods of dormancy in ectopic tissue sites before developing overt metastatic tumors. Accumulating evidence suggests that metastatic dormancy and recurrence of DTCs is regulated by intrinsic genetic instability and close interaction with the surrounding microenvironment. However, the mechanism by which DTCs enter and escape dormancy remains largely uncertain due to the lack of experimental model systems that can capture the initial activity of extremely rare DTCs. Here, we introduce a tissue-engineered approach to capture the critical events regulated by the extrinsic tissue microenvironments on DTCs with high experimental control and fidelity. We have developed human soluble factor available and richly vascularized microenvironments by subdermally implanting human bone marrow stromal cell pre-seeded scaffolds into an immunodeficient NSG mouse. Humanized tissue analogues recruited circulating human tumor cells released from physiologically relevant orthotopic prostate tumor xenograft. Tail-vein delivery of human peripheral blood mononuclear cells further increased cellular complexity. Established an early stage humanized metastatic niches were serially transplanted into a naïve NSG mouse to continuously monitor evolution of mature metastatic microenvironment. Our approach successfully recapitulated the heterogeneous phenotypes, dormant and aggressive, of DTCs and demonstrated human stromal and immune cell derived niche regulation. We envision that the controlled, analytical, and transplantable features of tissue-engineered humanized tumor microenvironments will be an invaluable tool for studying rare DTC biology, potentially leading to anti-metastatic strategies that target the tumor microenvironment.