Abstract A27: Heterotypic 3D bioprinted tissues to interrogate tumor-microenvironment crosstalk in cancer

Abstract

Abstract The tumor microenvironment is composed of multiple cell types (e.g., fibroblast, vascular, and immune cells), extracellular matrix (ECM) proteins, and signaling molecules that critically influence tumor cell phenotypes. The study of isolated tumor cells in culture has contributed to the discovery of oncogenes and tumor suppressors that regulate oncogenic phenotypes. As tumors develop, however, cancer cells secrete factors that functionally reprogram the genetically “normal” stromal cells in their environment. These tumor-associated stromal cells then further alter the microenvironment, providing tumor-stromal cell and tumor-ECM interactions that critically regulate tumor behaviors such as early tumor initiation, metastatic 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, bone marrow-derived mesenchymal stem cells, and endothelial cells can be incorporated into bioprinted tissues with defined architecture. We found that cells within these structures exhibit a tissue-like cellular density, proliferate, deposit ECM, migrate, and respond to extrinsic signals. Cells within these tissues self-organize to form complex structures, as indicated by nascent endothelial networks, and respond to extrinsic signals. We assessed intrinsic, extrinsic, and spatial tumorigenic phenotypes including cell survival, cell proliferation, differentiation state, ECM deposition, and cellular migration within these tissues in response to extrinsic signals or therapies. Together, this work demonstrates that bioprinted tumor tissue models recapitulate many aspects of in vivo neoplastic tissues. We are continuing to use 3D bioprinted tumor tissues, leveraging the manipulable nature of these models to interrogate the role of distinct tumor microenvironments on tumor cell phenotypes including proliferation, migration, and response to therapies. In pancreatic cancer models, we have printed tissues containing pancreatic stellate cells with and without knockdown of the prolyl isomerase PIN1, which we show inhibits stellate cell activation. We show that loss of PIN1 in the stellate cells surrounding the tumor has effects not only on activation markers of fibroblasts, but also on tumor, endothelial, and immune phenotypes within the tissues. Further work is focused on characterizing the signals that drive these changes. Citation Format: Ellen M. Langer, Isabel A. English, Megan A. Turnidge, Zinab O. Doha, Rosalie C. Sears. Heterotypic 3D bioprinted tissues to interrogate tumor-microenvironment crosstalk in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A27.