{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:03:30Z","timestamp":1789344210189,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003382","name":"Core Research for Evolutional Science and Technology","doi-asserted-by":"publisher","award":["JPMJCR19H5"],"award-info":[{"award-number":["JPMJCR19H5"]}],"id":[{"id":"10.13039\/501100003382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008886","name":"Princess Takamatsu Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008886","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["2022048307"],"award-info":[{"award-number":["2022048307"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22H02828"],"award-info":[{"award-number":["22H02828"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K11153"],"award-info":[{"award-number":["24K11153"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic options and poor clinical outcomes. Although PDAC has traditionally been thought to arise from ductal epithelial cells, recent studies using genetically engineered mouse models have demonstrated that acinar cells can also serve as a cell of origin, giving rise to tumors with distinct biological properties. Here, we investigated whether such lineage\u2010specific differences are preserved in human PDAC. RNA sequencing was performed on resected specimens from 40 treatment\u2010na\u00efve patients with PDAC, and tumors were classified into Acinar\u2010 and Ductal\u2010subtypes using lineage\u2010specific gene expression signatures derived from mouse models. This classification strategy was further applied to human PDAC cell lines, followed by in\u00a0vitro drug sensitivity assays. Patients with Acinar\u2010subtype tumors had significantly longer overall survival than those with Ductal\u2010subtype tumors (median, 54.0 vs. 26.5\u2009months;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), and multivariate analysis identified the ductal cell\u2010derived tumor signature as an independent predictor of poor prognosis (HR, 3.74 [95% CI, 1.41\u20139.97];\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01). Among patients who developed postoperative recurrence, Acinar\u2010subtype tumors were associated with more durable disease control (\u2265\u200910\u2009months) following gemcitabine\u2010based chemotherapy than Ductal\u2010subtype tumors (63.6% vs. 16.7%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02). Consistently, pancreatic cancer cell lines classified as Acinar\u2010subtype showed greater sensitivity to gemcitabine (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) and paclitaxel (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). These findings extend the clinical relevance of cell\u2010of\u2010origin signatures beyond prognostic stratification, highlighting the potential of cell\u2010of\u2010origin\u2010based classification for treatment stratification and precision medicine in PDAC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70533","type":"journal-article","created":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:27:28Z","timestamp":1789342048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Significance of a Cell\u2010Of\u2010Origin\u2010Based Classification in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-4371","authenticated-orcid":false,"given":"Tatsuya","family":"Kikuchi","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Ako","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"},{"name":"Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironari","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Okayama City Hospital  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kinugasa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Hirai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Matsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Terasawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"},{"name":"Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyuki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Tsutsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Horiguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"},{"name":"Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Yasui","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Fuji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosei","family":"Takagi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Kato","sequence":"additional","affiliation":[{"name":"Bioinformatics Analysis Center Kagawa University, Kagawa  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumio","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoyuki","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"7","article-title":"Cancer Statistics, 2022","volume":"72","author":"Siegel R. 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D.","year":"2013","journal-title":"New England Journal of Medicine"},{"issue":"19","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX Versus Gemcitabine for Metastatic Pancreatic Cancer","volume":"364","author":"Conroy T.","year":"2011","journal-title":"New England Journal of Medicine"},{"issue":"4","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1101\/gad.275776.115","article-title":"Genetics and Biology of Pancreatic Ductal Adenocarcinoma","volume":"30","author":"Ying H.","year":"2016","journal-title":"Genes & Development"},{"issue":"9","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a031435","article-title":"KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer","volume":"8","author":"Waters A. M.","year":"2018","journal-title":"Cold Spring Harbor Perspectives in Medicine"},{"issue":"2","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ccell.2017.07.007","article-title":"Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma","volume":"32","author":"Cancer Genome Atlas Research Network, Electronic Address Aadhe, Cancer Genome Atlas Research N","year":"2017","journal-title":"Cancer Cell"},{"issue":"4","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nm.2344","article-title":"Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy","volume":"17","author":"Collisson E. 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A.","year":"2015","journal-title":"Nature Genetics"},{"issue":"7592","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic Analyses Identify Molecular Subtypes of Pancreatic Cancer","volume":"531","author":"Bailey P.","year":"2016","journal-title":"Nature"},{"issue":"2","key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41588-019-0566-9","article-title":"Transcription Phenotypes of Pancreatic Cancer Are Driven by Genomic Events During Tumor Evolution","volume":"52","author":"Chan\u2010Seng\u2010Yue M.","year":"2020","journal-title":"Nature Genetics"},{"issue":"6","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2018.08.033","article-title":"Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features","volume":"155","author":"Puleo F.","year":"2018","journal-title":"Gastroenterology"},{"issue":"6","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1136\/gutjnl-2018-317706","article-title":"Experimental Microdissection Enables Functional Harmonisation of Pancreatic Cancer Subtypes","volume":"68","author":"Maurer C.","year":"2019","journal-title":"Gut"},{"issue":"1","key":"e_1_2_12_18_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s43018-019-0010-1","article-title":"A Unifying Paradigm for Transcriptional Heterogeneity and Squamous Features in Pancreatic Ductal Adenocarcinoma","volume":"1","author":"Hayashi A.","year":"2020","journal-title":"Nature Cancer"},{"issue":"4","key":"e_1_2_12_19_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41575-019-0109-y","article-title":"Molecular Subtypes of Pancreatic Cancer","volume":"16","author":"Collisson E. 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M.","year":"2017","journal-title":"Cell Reports"},{"issue":"10041","key":"e_1_2_12_23_1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0140-6736(16)30583-9","article-title":"Adjuvant Chemotherapy of S\u20101 Versus Gemcitabine for Resected Pancreatic Cancer: A Phase 3, Open\u2010Label, Randomised, Non\u2010Inferiority Trial (JASPAC 01)","volume":"388","author":"Uesaka K.","year":"2016","journal-title":"Lancet"},{"issue":"4","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10147-023-02317-x","article-title":"Clinical Practice Guidelines for Pancreatic Cancer 2022 From the Japan Pancreas Society: A Synopsis","volume":"28","author":"Okusaka T.","year":"2023","journal-title":"International Journal of Clinical Oncology"},{"key":"e_1_2_12_25_1","volume-title":"TNM Classification of Malignant Tumours","author":"Brierley J. 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