{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:40:47Z","timestamp":1788435647581,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W\/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14\/P53\/P21 and P16\/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.<\/jats:p>","DOI":"10.3390\/cancers13205139","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"5139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome"],"prefix":"10.3390","volume":"13","author":[{"given":"Jessica","family":"Merkle","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2817-1974","authenticated-orcid":false,"given":"Markus","family":"Breunig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Allg\u00f6wer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7902-590X","authenticated-orcid":false,"given":"Michael K.","family":"Melzer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"},{"name":"Department of Urology, Ulm University, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Bens","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ulm University & Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiner","family":"Siebert","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ulm University & Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0484-0974","authenticated-orcid":false,"given":"Lukas","family":"Perkhofer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ninel","family":"Azoitei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-2646","authenticated-orcid":false,"given":"Sandra","family":"Heller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Meier","sequence":"additional","affiliation":[{"name":"Helmholtz Pioneer Campus, Helmholtz Zentrum M\u00fcnchen, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0592-5232","authenticated-orcid":false,"given":"Alexander","family":"Kleger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0640-0764","authenticated-orcid":false,"given":"Meike","family":"Hohwieler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of pancreatic cancer: Global trends, etiology and risk factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. 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