Abstract A15: Elucidating the role of p53 in the cellular origins of pancreatic cancer development

Abstract

The tumor suppressor gene TP53 encodes a transcriptional activator critical for suppressing pancreatic ductal adenocarcinoma (PDAC). TP53 mutations, which are most frequently missense mutations in the DNA binding domain, result in both loss of wild-type p53 function and gain of novel, oncogenic functions. Mouse models of PDAC relying on oncogenic Kras and p53 mutation have suggested that either pancreatic acinar or ductal cells, the two major epithelial cell types in the pancreas, may be the cell of origin for PDAC, although there is very limited understanding of the molecular pathways through which p53 mutations contribute to PDAC driven by oncogenic Kras. Moreover, the cellular functions of p53 involved in tumor suppression remain enigmatic. To set up a platform for deconstructing p53 loss-of-function (LOF) and gain-of-function (GOF) pathways, we have generated mouse models to study p53 function in adult mice, mimicking the context of human cancer, using tamoxifen-inducible Cre recombinases to activate Kras (KrasLSL-G12D) in adult mouse pancreatic acinar (Ptf1aCreER) and ductal (Sox9CreER) compartments, in the backdrop of different p53 alleles. To investigate p53 LOF, we generated mouse cohorts with wild-type p53 expression or conditional p53 knockout (p53fl/fl). To examine p53 GOF, we generated mouse cohorts with conditional expression of structural mutant p53R172H (p53LSL-R172H/fl), contact mutant p53R270H (p53LSL-R270H/fl) and conditional p53 knockout (p53null/fl) for comparison in a uniform p53 heterozygous genetic background of stromal tissues. Our tumor studies have demonstrated that oncogenic Kras expression and p53 knockout or mutation in acinar cells of adult mice leads to metastatic PDAC development with complete penetrance. This suggests a novel role for p53 in tumor suppression by blocking cellular reprogramming of acinar cells to ductal-like cells. In contrast, these mutations drive PDAC from ductal cells less efficiently. To understand the origins of human PDAC, we are investigating the molecular pathways altered in mouse acinar and ductal cell-derived tumors. Through comparison with human pancreatic cancer data, our studies will elucidate the cellular origins of different molecular subtypes of human PDAC. Elucidating the mechanisms of PDAC development is critical to improving detection and therapy in PDAC patients. Citation Format: Brittany M. Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura D. Wood, Laura D. Attardi. Elucidating the role of p53 in the cellular origins of pancreatic cancer development [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 A15.