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Breunig, M.* ; Merkle, J.* ; Wagner, M.* ; Melzer, M.K.* ; Barth, T.F.E.* ; Engleitner, T.* ; Krumm, J.* ; Wiedenmann, S. ; Cohrs, C.M. ; Perkhofer, L.* ; Jain, G.* ; Krüger, J.* ; Hermann, P.C.* ; Schmid, M.* ; Madácsy, T.* ; Varga, A.* ; Griger, J.* ; Azoitei, N.* ; Müller, M.* ; Wessely, O.* ; Robey, P.G.* ; Heller, S.* ; Dantes, Z.* ; Reichert, M.* ; Günes, C.* ; Bolenz, C.* ; Kuhn, F.* ; Maléth, J.* ; Speier, S. ; Liebau, S.* ; Sipos, B.* ; Kuster, B.* ; Seufferlein, T.* ; Rad, R.* ; Meier, M. ; Hohwieler, M.* ; Kleger, A.*

Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

Cell Stem Cell 28, 1105-1124.e19 (2021)

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Personalized in vitro models for dysplasia and carcinogenesis in the pancreas have been constrained by insufficient differentiation of human pluripotent stem cells (hPSCs) into the exocrine pancreatic lineage. Here, we differentiate hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. PDLOs are generated from hPSCs inducibly expressing oncogenic GNAS, KRAS, or KRAS with genetic covariance of lost CDKN2A and from induced hPSCs derived from a McCune-Albright patient. Each oncogene causes a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone form heterogenous dysplastic lesions or cancer, KRAS with CDKN2A loss develop dedifferentiated pancreatic ductal adenocarcinomas. In contrast, transplanted PDLOs with mutant GNAS lead to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cdkn2a ; Gnas ; Ipmn ; Kras ; Pdac ; Disease Modelling ; Ductal Pancreatic Organoids ; Human Pluripotent Stem Cells ; In Vitro Differentiation ; Xenograft; Oncogene-induced Senescence; Cellular Senescence; Distinct Tumor; Mouse; Emt; Differentiation; Progenitors; Suppression; Progression; Mutations

ISSN (print) / ISBN 1934-5909

e-ISSN 1875-9777

Journal Cell Stem Cell

Quellenangaben Volume: 28, Issue: 6, Pages: 1105-1124.e19

Publisher Cell Press

Publishing Place Cambridge, Mass.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)
Institute for Pancreatic Beta Cell Research (IPI)

Grants Else Kroner-Fresenius-Stiftung
German Cancer Aid
Baden-Wurttemberg-Foundation ExPoChip
INDIMED-Verbund PancChip
Ulm University
European Research Council
EU Horizon 2020
Hungarian Academy of Sciences
Paul Langerhans Institute Dresden (PLID) of Helmholtz Zentrum Munchen at the University Clinic Carl Gustav Carus of Technische Universitat Dresden
German Cancer Aid (Max Eder Program, Deutsche Krebshilfe)
DIR of the NIDCR, a part of the IRP, NIH, DHHS
DFG
Deutsche Forschungsgemeinschaft (DFG)