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Abstract IA14: Deconstructing the origins of PDAC development

The TP53 gene, which encodes the p53 transcription factor, is mutated in ~75% of human pancreatic ductal adenocarcinomas (PDACs), underscoring the fundamental role of p53 as a barrier to PDAC development. Despite this critical function, however, the cellular and molecular programs through which p53 acts in pancreatic cancer suppression remain poorly understood. To gain a better understanding of the pathways through which p53 acts to suppress PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to determine whether p53 acts in acinar and/or ductal cells to restrain PDAC development. Importantly, for these experiments we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 deletion and p53 missense mutations in driving cancer from these different cells of origin. This comprehensive analysis of large adult mouse cohorts has helped to define the cell of origin for PDAC and the effects of different p53 mutations on spontaneous PDAC development. To gain additional insight into the programs that become dysregulated during pancreatic cancer development, we have performed RNA-sequencing analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies are helping us to better understand the paths to PDAC development in humans and the underlying origins of different subtypes of this disease. Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura Wood, Laura D. Attardi. Deconstructing the origins of PDAC development [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA14.