Recapitulating Pancreatic Tumor Microenvironment through Synergistic Use of Patient Organoids and Organ‐on‐a‐Chip Vasculature. (8th June 2020)

• Record Type: Journal Article
• Authors: Lai, Benjamin Fook Lun; Lu, Rick Xing Ze; Hu, Yangshuo; Davenport Huyer, Locke; Dou, Wenkun; Wang, Erika Yan; Radulovich, Nikolina; Tsao, Ming Sound; Sun, Yu; Radisic, Milica
• Is Part Of: Advanced functional materials. Volume 30:Number 48(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-06-08
• Subjects: desmoplasia -- tumor microenvironment -- tumor organoids -- vascularized; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adfm.202000545
• Languages: English
• ISSNs: 1616-301X

Abstract

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. Abstract : An in vitro perfusable platform recapitulating a synergistic relationship between patient organoids and stromal fibroblasts is presented in a desmoplastic pancreatic tumor microenvironment. This co‐culture leads to increased extracellular remodeling and elevated collagen composition, resulting in an environment that imparts resistance to anticancer therapeutics via a restricted drug transport through the tumor tissue.