PuSH - Publication Server of Helmholtz Zentrum München: <em>Cdkn2a</em>-mutated pancreatic ductal organoids from induced pluripotent stem cells to model a cancer predisposition syndrome.

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Merkle, J.* ; Breunig, M.* ; Schmid, M.* ; Allgöwer, C.* ; Krüger, J.* ; Melzer, M.K.* ; Bens, S.* ; Siebert, R.* ; Perkhofer, L.* ; Azoitei, N.* ; Seufferlein, T.* ; Heller, S.* ; Meier, M. ; Müller, M.* ; Kleger, A.* ; Hohwieler, M.*

Cdkn2a-mutated pancreatic ductal organoids from induced pluripotent stem cells to model a cancer predisposition syndrome.

Cancers 13:5139 (2021)

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	Open Access Gold

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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 KRASG12D using 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 KRASG12D PDLO 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cdkn2a ; Familial Pancreatic Cancer ; Induced Pluripotent Stem Cells ; Pancreatic Organoids; Efficient Generation; Wild-type; High-risk; Melanoma; Mutations; Cdkn2a; Cycle; P16; Progenitors; Prevalence

ISSN (print) / ISBN 2072-6694

Journal Cancers

Quellenangaben Volume: 13, Issue: 20, Article Number: 5139

Publisher MDPI

Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)

Grants Clinician Scientist Program of Ulm University
Baden-Wurttemberg Foundation ExPoChip
German Cancer Aid
INDIMED-Verbund PancChip
Else Kroner-Fresenius-Stiftung
Bausteinprogramm of Ulm University
Deutsche Forschungsgemeinschaft (DFG)