Conclusion

The 3D in vitro vascularized IBC platforms presented in this work enabled us to dynamically characterize and model the IBC tumor-vascular interactions, as well as determine the spatiotemporal response of these interactions on vascular permeability and matrix porosity not possible with existing in vitro or in vivo models. The platforms provide a robust and cost-effective means to systematically and quantitatively investigate IBC in a controlled and replicable manner compared to the current standard of using PDX models. Using the in vitro platform, we determined IBC cells were more active in remodeling of the collagen ECM as well as secretion of proangiogenic and tumorigenic factor VEGF compared to non-IBC MDA-MB-231, revealing potential targets for IBC therapeutics. For the first time, we induced angiogenic sprouting of the vascular endothelium and vascular surrounding of tumor emboli (unique behaviors of IBC tumors) purely through tumor-endothelial cell interactions and characterized sprouting in a spatial and temporal fashion in an in vitro setting. Furthermore, our system captures blood vessel leakiness and increased matrix porosity, representative behavior of in vivo invasive tumors. With the in vitro vascularized IBC tumor platforms, behavioral variations that are representative of in vivo tumors can be identified and distinguished as a result of the different breast cancer cells. This platform allows for spatiotemporal imaging and identification of biological proteins and responses which may play a direct role in tumorigenesis and vascularization in vivo and represent a useful tool for studying various aggressive breast cancers whose phenotype is driven by tumor-stromal-vascular interactions. These platforms can be further expanded to investigate increasingly complex cell type interactions, thereby providing a tool to further decipher the mechanisms behind development of these tumors.