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For a detailed characterisation of PP cells, we aimed to establish PP cell lines. To this end, we generated a mouse model harbouring the SV40 large T antigen (TAg) in the <jats:italic>Rosa26<\/jats:italic> locus, which is expressed upon <jats:italic>Ppy<\/jats:italic>\u2010promoter\u2010mediated Cre\u2013loxP recombination. Whereas <jats:italic>Insulin1<\/jats:italic>\u2010<jats:italic>Cre<\/jats:italic>ERT\u2010mediated <jats:italic>TAg<\/jats:italic> expression in beta cells resulted in insulinoma, surprisingly, <jats:italic>Ppy<\/jats:italic>\u2010<jats:italic>Cre<\/jats:italic>\u2010mediated <jats:italic>TAg<\/jats:italic> expression resulted in the malignant transformation of <jats:italic>Ppy<\/jats:italic>\u2010lineage cells. These mice showed distorted islet structural integrity at 5\u2009days of age compared with normal islets. CK19<jats:sup>+<\/jats:sup> duct\u2010like lesions contiguous with the islets were observed at 2\u2009weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4\u2009weeks of age, suggesting that PDAC can originate from the islet\/endocrine pancreas. This was unexpected as PDAC is believed to originate from the exocrine pancreas. RNA\u2010sequencing analysis of <jats:italic>Ppy<\/jats:italic>\u2010lineage islet cells from 7\u2010day\u2010old <jats:italic>TAg<\/jats:italic><jats:sup><jats:italic>+<\/jats:italic><\/jats:sup> mice showed a downregulation and an upregulation of endocrine and exocrine genes, respectively, in addition to the upregulation of genes and pathways associated with PDAC. These results suggest that the expression of an oncogene in <jats:italic>Ppy<\/jats:italic>\u2010lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that <jats:italic>Ppy<\/jats:italic>\u2010lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. \u00a9 2024 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6295","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T04:25:10Z","timestamp":1717475110000},"page":"429-441","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of <scp><i>Ppy<\/i><\/scp>\u2010lineage cells as a novel origin of pancreatic ductal adenocarcinoma"],"prefix":"10.1002","volume":"263","author":[{"given":"Ofejiro Blessing","family":"Pereye","sequence":"first","affiliation":[{"name":"Laboratory of Developmental Biology and 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