Recapitulating Pancreatic Tumor Microenvironment through Synergistic Use of Patient Organoids and Organ‐on‐a‐Chip Vasculature

Abstract Tumor progression relies on the interaction between neoplastic epithelial cells and their surrounding stromal partners. This cell cross‐talk affects stromal development, and ultimately the heterogeneity impacts drug efficacy. To mimic this evolving paradigm, 3D vascularized pancreatic adenocarcinoma tissue is microengineered in a tri‐culture system composed of patient‐derived pancreatic organoids, human fibroblasts, and endothelial cells on a perfusable platform, situated in a 96‐well plate. Through synergistic engineering, the benefits of cellular fidelity of patient tumor organoids are combined with the flow control of an organ‐on‐a‐chip platform. Validation of this platform includes demonstrating the growth of pancreatic tumor organoids by monitoring the change in metabolic activity of the tissue. Investigation of the tumor microenvironment highlights the role of fibroblasts in symbiosis with patient organoids, resulting in a six‐fold increase of collagen deposition and corresponding increase in tissue stiffness in comparison to fibroblast free controls. The value of a perfusable vascular network is evident in drug screening, as perfusing gemcitabine into stiffened matrix does not show the dose‐dependent effects on decrease in tumor viability as those under static conditions. These findings demonstrate the importance of a dynamic synergistic relationship between patient cells with stromal fibroblasts, in a 3D perfused vascular network, to accurately recapitulate a dynamic tumor microenvironment.