{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T08:51:42Z","timestamp":1765875102285,"version":"3.48.0"},"reference-count":59,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T00:00:00Z","timestamp":1765670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"STI2030-Major Projects","award":["2021ZD0202400"],"award-info":[{"award-number":["2021ZD0202400"]}]},{"name":"National Science and Technology Major Program","award":["2024ZD0530500"],"award-info":[{"award-number":["2024ZD0530500"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["62472131"],"award-info":[{"award-number":["62472131"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["62172131"],"award-info":[{"award-number":["62172131"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["U23A20166"],"award-info":[{"award-number":["U23A20166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32570792"],"award-info":[{"award-number":["32570792"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["62502128"],"award-info":[{"award-number":["62502128"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Research and Development Program of Heilongjiang Province","award":["2024ZX12C27"],"award-info":[{"award-number":["2024ZX12C27"]}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M760709"],"award-info":[{"award-number":["2024M760709"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Heilongjiang Postdoctoral Fund","award":["LBH-Z24210"],"award-info":[{"award-number":["LBH-Z24210"]}]},{"name":"Longjiang New Era Outstanding Doctoral Dissertation Project","award":["LJYXL2024-069"],"award-info":[{"award-number":["LJYXL2024-069"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although single-cell analyses have advanced our understanding of pancreatic ductal adenocarcinoma (PDAC), most studies to date have focused on primary and metastatic tumors. Here, we map cell composition, phenotypic plasticity, and microenvironmental remodeling from human normal pancreas through preneoplastic lesions to PDAC, with the preneoplastic phase recognized as a critical window for carcinogenesis. We pinpoint genes that are persistently dysregulated throughout malignant transformation and are associated with a poor prognosis. Focusing on ductal and acinar cells as the principal origins of PDAC, we delineate malignant preneoplastic cell clusters that exhibit strong carcinogenic potential. Immune profiling reveals marked expansion and functional reprogramming of macrophages during disease progression. Integrative analysis with human PDAC bulk transcriptomic cohorts identifies candidate compounds, such as Brefeldin A, with potential for intervention in preneoplastic disease. Together, our study elucidates dynamic molecular and cellular mechanisms underlying PDAC carcinogenesis and provides actionable insights for early intervention and targeted therapy.<\/jats:p>","DOI":"10.3390\/ijms262412031","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:36:39Z","timestamp":1765791399000},"page":"12031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elucidating Pancreatic Ductal Adenocarcinoma Carcinogenesis at Single-Cell Resolution and Identifying Subtype Specific Drug Candidates"],"prefix":"10.3390","volume":"26","author":[{"given":"Jing","family":"Chen","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1699-2706","authenticated-orcid":false,"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuan","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiyue","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyao","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Lv","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bolin","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5331-8872","authenticated-orcid":false,"given":"Xinyi","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3709-3656","authenticated-orcid":false,"given":"Yunpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congxue","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/S0140-6736(17)33326-3","article-title":"Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries","volume":"391","author":"Allemani","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1093\/jnci\/djaa004","article-title":"Recent Trends in the Incidence and Survival of Stage 1A Pancreatic Cancer: A Surveillance, Epidemiology, and End Results Analysis","volume":"112","author":"Blackford","year":"2020","journal-title":"JNCI J. 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