Abstract C056: The initiation and progression of pancreatic ductal adenocarcinoma through a p53 lens

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of only 11%. Slated to be the 2nd most deadly cancer by 2026, pancreatic cancer survival rates have not improved substantially over the years. With a lack of early detection methods and a highly immunosuppressive tumor microenvironment (TME), PDAC tumors are highly resistant to treatment. Oncogenic mutations in KRAS are present in >90% of cases and mutations in the tumor suppressor gene TP53 are present in ~72% of cases. However, why p53 mutations are so prevalent and how they enhance PDAC development is not well understood. To elucidate how exactly p53 loss promotes PDAC, we are using genetically engineered mouse models combined with single-cell and spatial transcriptomic technologies. In this mouse model, PDAC is driven from adult acinar cells with a tamoxifen-inducible Ptf1aCreER allele by oncogenic Kras (KrasG12D) along with either p53 wild type (p53wt) or p53 deficiency (p53flox). In 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 and spatial transcriptomics to compare early stages of tumor development in the presence and absence of p53, and we will present our latest analyses. Providing insight into the early events of PDAC will lead to new approaches for improving clinical intervention in human PDAC. Citation Format: Kathryn J. Hanson, Allegra C. Minor, Brittany M. Flowers, Alyssa M. Kaiser, Nicholas Hughes, Hannes Vogel, Le Cong, Laura D. Attardi. The initiation and progression of pancreatic ductal adenocarcinoma through a p53 lens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C056.