In vitro multi-organ invasion model for exploring cardiac resistance to cancer metastasis

Despite the systemic spread of cancer, the ventricular myocardium is one of the least common sites of metastasis-a phenomenon that remains poorly understood. To examine this, we develop the Multi-organ Invasion Device (MInD), an organ-on-a-chip platform that enables multi-organ culture under flow. Organ compartments are connected in MInD using PermeoTubes-3D-printed porous conduits that support cancer cell intravasation, migration, and extravasation. In dual-organ devices, where highly aggressive breast cancer cells are co-cultured with either hepatic or cardiac tissue, invasion into cardiac tissue is significantly suppressed relative to hepatic co-culture. Importantly, in cardiac-hepatic-cancer tri-culture, the presence of cardiac tissue reduces overall invasion, with cancer cells preferentially migrating toward hepatic compartments. Cytokine profiling and RNA sequencing reveal that cardiac co-culture suppresses cell metastasis and invasion, while inducing immune activation. Overall, this platform presents an approach for uncovering organ-specific drivers of metastasis, accelerating future discovery of metastasis-inhibiting therapies.