Abstract PO-084: The role of p53 in the development of pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a very deadly cancer, with a 5-year survival rate of only 9%. This high mortality rate can be attributed to the lack of early detection methods and to tumors being resistant to treatment, in part due to a highly immunosuppressive tumor microenvironment (TME). The most commonly mutated genes in PDAC include activating mutations in KRAS in >90% of cases and mutations in the tumor suppressor TP53 gene in ~72% of cases. However, how p53, which is a transcription factor, normally suppresses PDAC progression is not well understood. Understanding the pathways through which p53 acts to suppress PDAC will provide key insight into the molecular mechanisms underlying PDAC initiation and progression. Our laboratory has recently shown in genetically engineered mouse models that Kras activation, coupled with p53 inactivation, can drive PDAC from either pancreatic acinar or ductal cells, with acinar cell- and ductal cell-derived tumor signatures resembling the classical and basal-like human PDAC subtypes, respectively. To better understand how p53 loss promotes PDAC, we are focusing on the acinar cell-derived PDAC mouse model and using single-cell transcriptomic technologies to ask in which cell states and through which pathways p53 acts to suppress PDAC development, in particular as PDAC has complex interactions between tumor cells and the TME. In this model, PDAC is driven by oncogenic Kras (KrasG12D) along with either p53 wild type (p53wt) or p53 deficiency (p53flox) in adult acinar cells by a tamoxifen-inducible Ptf1aCreER allele. In the progression of this model, acinar cells can give rise to PDAC likely through a transdifferentiation process called acinar-to-ductal metaplasia (ADM), which leads to pancreatic intraepithelial neoplasias (PanINs) and then PDAC. The initial cell fate transition, ADM, can be activated by growth factors, inflammation, and injury. We have conducted single cell RNA-sequencing (scRNA-seq) to compare early stages of tumor development in the presence and absence of p53. We have also conducted spatial transcriptomic analysis of these samples. Using these combined approaches, we are analyzing tumor cell populations and cells of the tumor microenvironment in the p53wt and p53flox genotypes and have found. We will present our latest single cell analyses on p53 dependent cell states and functional pathways during PDAC development. Understanding how tumor cell states and cells of the tumor microenvironment change with p53 status will reveal different paths of PDAC evolution and uncover novel approaches to improve clinical intervention for human PDAC. Citation Format: Kathryn J. Hanson, Brittany M. Flowers, Nicholas Hughes, Hannes Vogel, Le Cong, Laura D. Attardi. The role of p53 in the development of pancreatic ductal adenocarcinoma [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-084.