Abstract I15: Deciphering the origins of PDAC development

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 24_Supplement; p. I15
• Main Authors: Flowers, Brittany, Xu, Hang, Hanson, Kathryn, Curtis, Christina, Vogel, Hannes, Wood, Laura D., Attardi, Laura D.
• Format: Journal Article
• Language: English
• Published: 15.12.2019
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PANCA19-I15

Abstract The TP53 gene, encoding the p53 transcription factor, is mutated in the majority of human pancreatic cancers, underscoring its critical role as a barrier to PDAC development. Despite this essential function, however, the cellular and molecular pathways through which p53 acts in pancreatic cancer suppression have remained elusive. To gain a better understanding of the programs through which p53 suppresses 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 understand whether p53 acts in acinar and/or ductal cells to restrain PDAC development. For these studies 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 loss-of-function and gain-of-function mutations in driving cancer from these different cells of origin. In addition, we have characterized the trajectory of cancer development in these models through histologic analysis of lesions at different time points and through lineage tracing. This comprehensive analysis of large adult mouse cohorts has helped to define the role for p53 in restraining spontaneous PDAC development, an essential first step for understanding p53 programs involved in tumor suppression. To gain insight into the programs that become dysregulated during pancreatic cancer development, we have performed transcriptomic 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 will reveal 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 D. Wood, Laura D. Attardi. Deciphering the origins of PDAC 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 I15.