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

Author:

Pereye Ofejiro Blessing1,Nakagawa Yuko1,Sato Takashi1,Fukunaka Ayako1,Aoyama Shuhei2,Nishida Yuya2,Mizutani Wakana1,Kobayashi Nanami1,Morishita Yohei3,Oyama Tetsunari4,Kawabata‐Iwakawa Reika5,Watada Hirotaka2,Mizukami Hiroki6ORCID,Fukuda Akihisa7,Fujitani Yoshio1ORCID

Affiliation:

1. Laboratory of Developmental Biology and Metabolism, Institute for Molecular and Cellular Regulation (IMCR) Gunma University Gunma Japan

2. Department of Metabolism & Endocrinology Juntendo University Graduate School of Medicine Tokyo Japan

3. Laboratory for Analytical Instruments, Education and Research Support Centre Gunma University Graduate School of Medicine Gunma Japan

4. Department of Diagnostic Pathology Gunma University Graduate School of Medicine Gunma Japan

5. Division of Integrated Oncology Research Gunma University Initiative for Advanced Research Gunma Japan

6. Department of Pathology and Molecular Medicine, Biomedical Research Centre Hirosaki University Graduate School of Medicine Hirosaki Japan

7. Department of Gastroenterology and Hepatology Kyoto University Graduate School of Medicine Kyoto Japan

Abstract

AbstractThe Ppy gene encodes pancreatic polypeptide (PP) secreted by PP‐ or γ‐cells, which are a subtype of endocrine cells localised mainly in the islet periphery. 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 Rosa26 locus, which is expressed upon Ppy‐promoter‐mediated Cre–loxP recombination. Whereas Insulin1CreERT‐mediated TAg expression in beta cells resulted in insulinoma, surprisingly, PpyCre‐mediated TAg expression resulted in the malignant transformation of Ppy‐lineage cells. These mice showed distorted islet structural integrity at 5 days of age compared with normal islets. CK19+ duct‐like lesions contiguous with the islets were observed at 2 weeks of age, and mice developed aggressive pancreatic ductal adenocarcinoma (PDAC) at 4 weeks 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‐sequencing analysis of Ppy‐lineage islet cells from 7‐day‐old TAg+ 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 Ppy‐lineage cells induces a switch from endocrine cell fate to PDAC. Our findings demonstrate that Ppy‐lineage cells may be an origin of PDAC and may provide novel insights into the pathogenesis of pancreatic cancer, as well as possible therapeutic strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Funder

Japan Society for the Promotion of Science

Foundation for Promotion of Cancer Research

Publisher

Wiley

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