Identification of Ppy-lineage cells as a novel origin of pancreatic ductal adenocarcinoma

The Ppy-gene encodes the pancreatic polypeptide (PP) secreted by PP- or ?- cells, an endocrine cell type located in the islet periphery. For a detailed characterization of PP cells, we aimed to establish PP cell lines. To this end, we generated Ppy-Cre;Rosa26-CAG-LSL-Large T mice, in which the SV40 large T antigen (TAg) is expressed in Ppy-expressing cells upon Cre-loxP-mediated recombination. Ppy-Cre;Rosa26-CAG-LSL-Large T mice, surprisingly, developed pancreatic ductal adenocarcinoma (PDAC) rapidly by 3 to 4 weeks of age, while mice with insulin2-Cre-mediated activation of TAg developed insulinomas. This suggests that PDACs could arise from the islet/endocrine cells, which is rather unexpected as PDACs are generally believed to originate from the pancreatic acinar or ductal cells. RNA-seq analysis of transformed Ppy-lineage cells in 7-day old islets showed downregulation of endocrine genes, upregulation of exocrine, ductal genes, and upregulation of PDAC-related genes and pathways, respectively. These results suggest that expression of an oncogene in Ppy-lineage cells leads to a fate switch in these endocrine precursors that causes them to adopt a PDAC cell fate. Our findings revealed that Ppy-lineage cells may be one of the origins of PDAC and provide novel insights into the heterogeneity in pathogenesis of pancreatic cancer and its personalized therapy. Overall design: To determine the molecular characteristics and gene expression profile of Ppy-lineage lesion-forming cells, we performed RNA-seq and gene ontology analysis of Ppy-lineage cells with and without antigen activation using7-day oldreporter mice which express both tdTomato and TAg. We profiled total of 100 PpyCre/+; Rosa26tdTomato/+ (control) cells and 100 RTT (transformed) cells pooled from n=3 mice for each group using RNA-seq analysis.