Abstract C41: Establishment of a novel mouse model of pancreatic squamous carcinoma
Authors: Pinto Filipa , Pichardo Tachira , Leu Adrien , Senoo Makoto 
Published: March 2020

Pancreatic cancer is a lethal malignancy with the highest mortality rate among all cancers and a 5-year survival rate of 9% in the US. Among all subtypes of pancreatic cancers, the molecular mechanisms underlying the development of squamous carcinomas are not well understood. While pure squamous carcinoma makes up only 0.05-5% of all pancreatic cancers, it is very aggressive and leads to the worst prognosis among all pancreatic cancers. However, animal models to study the initiation and progression of pancreatic squamous carcinoma are lacking. Genetic studies have recently revealed the molecular signature of pancreatic cancers and identified the transcription factor p63 as a candidate that contributes to the development of pancreatic carcinomas. In one study (Bailey et al., Nature 2016;47-52), upregulation of the p63-mediated transcriptional network was reported. Another genome-wide analysis has identified a SNP in the p63 gene as a risk factor for the development of pancreatic cancers (Childs et al., Nat Genet 2015;911-6). Furthermore, it has been shown that expression of TAp63, an isoform of p63 with a tumor suppressor function, is frequently suppressed in pancreatic cancers (Bailey et al., Nature 2016;47-52). While p63 is rarely mutated in human cancers, ΔNp63α, the predominant isoform of p63 in epithelia, is overexpressed in a variety of human cancers of squamous cell origin. Notably, although p63 proteins are not expressed in normal pancreatic cells, they are expressed at high levels in areas of squamous differentiation of pancreatic cancers (Basturk et al., Modern Pathol 2005;1193-8). We hypothesize that aberrant expression of ΔNp63α in the pancreatic epithelia drives the tumorigenesis of pancreatic squamous carcinomas. To test this hypothesis, we have created transgenic (Tg) mice conditionally expressing ectopic ΔNp63α upon crossing with tissue/cell type-specific Cre-Tg mice in the presence of the K-rasG12D mutation (Hingorani et al., Cancer Cell 2003;437-50), a pancreatic cancer-promoting factor. Our data show that Pdx1Cre:KrasG12D:ΔNp63α-Tg mice develop pancreatic squamous carcinoma as determined by the cellular morphology and the shift of the expression of cytokeratin 8 (K8), a pan-pancreatic epithelial cell marker, into K5, a squamous epithelial cell marker. Interestingly, the absence of the K-ras mutation did not lead to the development of pancreatic tumors, indicating that de novo expression of ΔNp63α alone is not sufficient for the generation of pancreatic squamous carcinomas. None of the mice in our control cohort of the Pdx1Cre:KrasG12D:p53+/- genotype (Bardeesy et al., PNAS 2006;5947-52) developed pancreatic squamous carcinomas or showed p63 expression, emphasizing the functional differences between the two p53 family members. We aim to further characterize our novel animal model and determine the molecular mechanisms by which p63 contributes to the squamous pathogenesis of pancreatic cancer.

Citation Format: Filipa Pinto, Tachira Pichardo, Adrien Leu, Makoto Senoo. Establishment of a novel mouse model of pancreatic squamous carcinoma [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 C41.