Abstract IA-06: Heterotypic 3D bioprinted tissues to study pancreatic cancer

Abstract

Abstract Crosstalk between tumor cells and the tumor microenvironment contributes critically to tumor initiation, tumor progression, and therapeutic response. The tumor microenvironment (TME) is composed of multiple cell types (e.g. fibroblast, vascular, and immune cells) that are temporally and spatially dynamic. Stromal cells in the TME respond not only to the growing tumor cells, but are also affected by concurrent changes in the accessibility and composition of the extracellular matrix (ECM), signaling molecules, nutrients and oxygen. Together, the interactions of tumor cells and stromal cells regulates the tumor phenotype and, ultimately, affects patient outcomes. As more is understood about the dynamic relationship of multiple cell types in the tumor microenvironment, it has become clear that better models of human cancer are needed. In order to understand the impact of heterotypic crosstalk on tumor behaviors such as initiation, progression, and response to therapies, we recently developed heterotypic, scaffold-free tissue models of advanced cancer using an extrusion-based bioprinter system. Multiple cell types including cancer cells, fibroblasts, endothelial cells, mesenchymal stem cells, and immune cells can be incorporated into bioprinted tissues with defined spatial architecture, and the system is compatible with patient-derived cells. Within these structures, cells exhibit a tissue-like cellular density, deposit ECM, and self-organize to form complex structures, as illustrated by formation of nascent endothelial networks. Cell intrinsic, extrinsic, and spatial phenotypes, including cell survival, cell proliferation, differentiation state, ECM deposition, and cellular migration, can be assessed within these tissues following exposure to extrinsic signals or therapies. Our current work is focused in three main areas. First, we aim to understand the signaling between tumor and stromal cell types in early cancer development that contributes to malignant progression. Second, we are working to understand the influence of fibroblast heterogeneity on tumor cell phenotypes, using genetic or non-genetic perturbagens to alter fibroblast activation. Finally, we are building tissues comprising patient-derived cells to understand how the microenvironment influences therapeutic response. Together, our work demonstrates that bioprinted tumor tissues recapitulate many aspects of in vivo neoplastic tissues, and provides a manipulable model system to interrogate molecular mechanisms of tumor development, progression, and treatment response. Citation Format: Ellen M Langer, Brittany L Allen-Petersen, Isabel A English, Jason M Link, Rosalie C Sears. Heterotypic 3D bioprinted tissues to study pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-06.