Tissue engineering technologies provide controllable and reproducible approaches to reconstruct the extracellular and cellular elements of pancreatic cancer. In a reductionist approach they allow the modelling of the complex tumor microenvironment (TME) and the study of disease biology and anti-cancer treatments. Our objective is that an engineered TME model, that mimics the tissue and matrix composition, architecture and cell types, will behave like a real tumor and is suitable for preclinical drug testing. Using biomimetic materials, we recreated the desmoplastic tissue characteristics of the pancreatic TME. Our natural and synthetic biomaterials were tailored to achieve the mechanical properties that resembled the stiffness and viscoelasticity of patient-derived tissues, providing a supportive cell-matrix interface for 3D cell culture conditions. Pancreatic cancer cells grown embedded in the matrix scaffolds formed tumor spheroids. Cell-based assays and microscopic analysis indicated a high cell viability and proliferation of the tumor spheroids as well as the expression of cancer-associated markers. Incorporation of cancer-associated fibroblasts and myeloid cells led to a multicellular 3D systems and matrix stiffening due to the secretion of extracellular matrix proteins. Transcriptomic analysis of the 3D cell cultures identified differentially regulated pathways related to cell proliferation, mechano-transduction and the secretion of pro-inflammatory cytokines, indicative of a malignant behavior. Treatment with mechano-modulating inhibitors and anti-cancer compounds increased the efficacy of chemotherapeutics, thereby reducing matrix stiffness and the release of cytokines. Our engineered TME model provides an easily translatable technology to ease the burden of pancreatic cancer, allowing us to characterize combination treatments that slow down or reduce tumor growth.

Citation Format: Rodrigo Curvello, Verena Kast, Daniela Loessner. Modeling the tumor microenvironment using tissue engineering technologies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-069.