Abstract PR03: Mutant p53 promotes adenocarcinoma in pancreatic ductal cells

Abstract Background: The “cell of origin” for pancreatic “ductal” neoplasia remains uncertain. Selective activation of Kras in the acinar cell compartment robustly generates mPanIN lesions, while similar activation in pancreatic ductal epithelial cells produces minimal change. These differences are notable considering in human tumorigenesis, mutational oncogene activation is postulated to occur in either single cells or small numbers of cells, followed by clonal expansion and tumor initiation. We have interrogated the comparative ability of adult pancreatic acinar and duct cells to respond to oncogenic Kras using Hnf1b:CreERT2 and Mist1:CreERT2 mice, and applied comprehensive bioinformatics analysis to identify mechanisms of duct cell-specific Kras resistance. Hypothesis and Methods: We hypothesized that duct cell-specific changes in gene expression would mediate the relative resistance of ductal epithelial cells to Kras-mediated transformation. To identify these changes, we studied the initiation and progression of pancreatic cancer with unprecedented temporal and spatial resolution. Our approach allows for the direct visualization and FACS-based isolation of specific cell populations in which oncogenic Kras has been activated. We have activated KrasG12D and a membrane-tethered GFP in a number of adult pancreatic cell types including the acinar, ductal and centroacinar cells. Using FACS-based isolation and visualization, we have generated whole transcriptome signatures of how the different cell types respond to Kras over time. Our comprehensive bioinformatic approach involves the identification of genes that are increased or decreased at different time points after the induction of oncogenic Kras expression. Results: Kras activation in the adult acinar cells resulted in brisk PanIN formation, while no evidence of pancreatic neoplasia was observed for up to 6 months following isolated Kras activation in Hnf1b+ duct cells. By comparing gene expression changes occurring following Kras activation in acinar vs. duct cells, we identified a panel of candidate duct cell-specific Kras resistance genes. These included Bcl-2, p21, Stk3, Plkha1, Slc9a9 and Pdcd10. Identification of upregulated Bcl-2 and p21 expression following Kras activation in duct cells, but not acinar cells, suggested involvement of the p53 pathway as a cell type-specific suppressor of pancreatic neoplasia. We recently published that biallelic expression of mutant p53R172H in cooperation with KrasG12D led to the development of pancreatic cancer from ductal cells. We are now investigating both autocrine and paracrine signaling mechanisms of mutant p53 oncogenic transformation in human derived ductal epithelial cells. This abstract is also being presented as Poster A17 Citation Format: Kishore Polireddy, Audrey Hendley, Melissa A. Pruski, Kelly Lafaro, Mamoun Younes, Anirban Maitra, Florencia McAllister, Christine A. Iacobuzio-Donahue, Wasim A. Dar, John S. Bynon, Steven D. Leach, Jennifer M. Bailey.{Authors}. Mutant p53 promotes adenocarcinoma in pancreatic ductal cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr PR03.