Abstract IA11: Pancreatic cancer biology and medicine

Abstract

Abstract Pancreatic cancer remains the most deadly of the common malignancies. To increase our basic understanding of this disease and advance medical approaches, we have recently co-developed with Hans Clevers mouse and human organoid model systems. Our organoid cultures representative of either normal or neoplastic ductal cells facilitate the systematic analysis of neoplastic biochemical cascades, provide a platform to explore therapeutic and diagnostic strategies, and also enable the reconstitution of tumor microenvironment interactions. We have found that Nrf2, a principal regulator of redox metabolism, promotes proliferation in KRAS mutant pancreatic ductal cells in part by regulating the reduced state of the cellular proteome. As a consequence of proteome oxidation, central pathways of homeostasis are impaired, including protein translation. The genes with markedly impaired translation include a number of critical proto-oncogenes. Additionally, diagnostic and therapeutic approaches have revealed new avenues to explore for early detection and disease treatment. Finally, the co-culture of organoids with pancreatic stellate cells promotes the activation of each cell type and results in the production of extracellular matrix. Co-cultures reveal distinct subtypes of stellate cells and provide an opportunity to identify and target novel mediators of the tumor microenvironment. Citation Format: David Tuveson.{Authors}. Pancreatic cancer biology and medicine. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA11.