Multi-Organ-on-Chip approach to exploring breast cancer liver metastases concerning the endothelial barrier and the influence of immune cells.

Cancer metastasis is the spread of cancerous cells through the circulatory system to distant organs. Existing in vitro models remain insufficient to faithfully reproduce the metastatic process. Multi-Organ-on-Chip (multi-OoC) platforms allow the integration of complex tissue models. Here, we propose a microplatform that recapitulates breast cancer (BC) migration to the liver, considering an endothelial barrier (EB) and immune cell interactions. Tissue micromodels were created using agarose multi-wells, loaded into the microplatform, and separated by different types of barriers: (i) collagen type I, (ii) cell culture medium, (iii) immune (Jurkat) cells, (iv) a microvessel, and (v) a microvessel perfused with Jurkat cells. Spatial arrangement of cells, their morphology, and viability were imaged using fluorescence microscopy over 10-day experiments. Quantitative data such as Feret Diameter, relative Raw Integrated Density (ID) and migration distance of tumor cells (GFP-MDA-MB-231) were evaluated. The concentrations of metastatic agents (interleukin-6 (IL-6), and interleukin-11 (IL-11)) were determined using ELISA. The potential of a microplatform in drug screening was preliminarily assessed with the use of Doxorubicin (Dox) over a 7-day experiment. Changes in Feret diameter and ID indicated a gradual disintegration of the BC micromodel. BC cells migrated toward the liver micromodel through a barrier formed in the central microchannel. An EB was impenetrable for GFP-MDA-MB-231, whereas Jurkat cells promoted the migration of BC cells. Dox induced transient inflammation and suppressed IL-11-dependent pro-metastatic signaling, consistent with its dual cytotoxic and immunomodulatory roles.