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.