Abstract

Tissue Engineered Microenvironments For Studying Human Tumor Metastasis

Jungwoo Lee, Assistant Professor, University of Massachusetts-Amherst

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. Yet, the mechanism by which DTCs enter and escape dormancy remains largely uncertain due to the lack of model systems that can capture the initial activity of extremely rare DTCs. Here, we introduce a bioengineered approach to capture the critical events regulated by the extrinsic tissue microenvironments on DTCs with high experimental control and fidelity. We first developed human soluble factor enriched and vascularized microenvironments by subdermally implanting human bone marrow stromal cell preseeded scaffolds into immunodeficient NSG mice. Humanized tissue analogues recruited circulating human tumor cells released from physiologically relevant orthotopic xenograft tumors. Tail-vein delivery of human peripheral blood mononuclear cells further increased cellular complexity. Established human stromal-tumor-immune niches were serially transplanted into naïve NSG mice for continuous monitoring of metastatic tumor development. Our approach successfully recapitulated the heterogeneous phenotypes, dormant and aggressive, of DTCs and demonstrated human stromal and immune cell derived niche regulation.