An Engineered Paper‐Based 3D Coculture Model of Pancreatic Cancer to Study the Impact of Tissue Architecture and Microenvironmental Gradients on Cell Phenotype

• Published in: Advanced healthcare materials 2023-06, Vol.12 (14), p.e2201846-n/a
• Main Authors: Cadavid, Jose L., Latour, Simon, Nowlan, Ferris, Co, Ileana L., Landon‐Brace, Natalie, Wouters, Bradly G., Grünwald, Barbara T., Nitz, Mark, Jackson, Hartland Warren, McGuigan, Alison P.
• Format: Article
• Language: English
• Subjects: 3D model; Adenocarcinoma; Cancer; Carcinoma, Pancreatic Ductal - pathology; Cell culture; Cell interactions; Coculture Techniques; fibroblasts; Genotype & phenotype; Heterogeneity; Humans; Hypoxia; Organoids; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; patient‐derived organoids; Phenotype; Phenotypes; Stellate cells; Stromal cells; Three dimensional models; tissue architecture; Tumor Microenvironment; Tumors
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.202201846

The spatial configuration of cells in the tumor microenvironment (TME) affects both cancer and fibroblast cell phenotypes contributing to the clinical challenge of tumor heterogeneity and therapeutic resistance. This is a particular challenge in stroma‐rich pancreatic ductal adenocarcinoma (PDAC). Here, a versatile system is described to study the impact of tissue architecture on cell phenotype using PDAC as a model system. This fully human system encompassing both primary pancreatic stellate cells and primary organoid cells using the TRACER platform to allow the creation of user‐defined TME architectures that have been inferred from clinical PDAC samples and are analyzed by CyTOF to characterize cells extracted from the system. High dimensional characterization using CyTOF demonstrates that tissue architecture leads to distinct hypoxia and proliferation gradients. Furthermore, phenotypic markers for both cell types are also graded in ways that cannot be explained by either hypoxia or coculture alone. This demonstrates the importance of using complex models encompassing cancer cells, stromal cells, and allowing control over architecture to explore the impact of tissue architecture on cell phenotype. It is anticipated that this model will help decipher how tissue architecture and cell interactions regulate cell phenotype and hence cellular and tissue heterogeneity. This paper describes the development and characterization of an engineered 3D coculture model (TRACER) of pancreatic cancer that recreates in‐vitro the different stroma‐tumor architecture found in patient's tumors. By combining the modular design of TRACER and the versatility of mass cytometry, the effect of the tumor architecture and of microenvironmental gradients on cell behavior can be examined.