Abstract I25: Understanding and exploiting natural barriers to pancreatic tumorigenesis

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily aggressive cancer that arises in the context of a unique tumor microenvironment. Molecularly, PDAC involves a combination of undruggable cancer drivers, including activating mutations in the KRAS oncogene and disruption of tumor suppressors such a TP53, SMAD4, and CDKN2A together with poorly characterized epigenetic changes that correlate with metastatic progression. Histologically, PDAC arises within a heterogeneous tissue microenviroment characterized by dense fibroinflammatory stroma that influences disease progression and limits therapy response. Our laboratory has developed genetically engineered mouse models based on ES cells (GEMMESCs) of pancreas cancer, where chimeric mice are produced directly from multiallelic ES cells harboring a latent KrasG12D oncogene together with all the genetic elements needed for Kras activation in the together with those needed for tetracycline-inducible (and reversible) regulation of short hairpin RNAs targeting capable of suppressing any gene of interest at any time after pancreas cancer initiation. Using this system, we have probed the epigenetic requirements for pancreas cancer initiation and compare them to those required for pancreatic regeneration following tissue damage; in addition, we have explored the metabolic programs needed for p53 to suppress tumorigenesis. Our studies have identified elements of cellular plasticity that act at multiple points that suppress pancreas cancer progression and identify actionable intervention points required for these transitions. Citation Format: Scott W. Lowe. Understanding and exploiting natural barriers to pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I25.