Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells
| Autor: | Zahra Dantes, Maximilian Reichert, József Maléth, Thomas Engleitner, Thomas Seufferlein, MK Melzer, Christian M. Cohrs, J Merkle, Martin Wagner, Martin Müller, Tamara Madácsy, Joscha Griger, Cagatay Günes, Stefan Liebau, Markus Breunig, Matthias Meier, Thomas F. E. Barth, Sandra Wiedenmann, Patrick C. Hermann, Stephan Speier, Bernhard Kuster, Sandra Heller, Maximilian Schmid, Gaurav Jain, Pamela Gehron Robey, Johannes Krumm, Florian Kuhn, Lukas Perkhofer, Christian Bolenz, Oliver Wessely, Alexander Kleger, Bence Sipos, Árpád Varga, Ninel Azoitei, Roland Rad, Jana Krüger, Meike Hohwieler |
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| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
Proteomics 03. Orvos- és egészségtudomány medicine.disease_cause Article 03 medical and health sciences Mice 0302 clinical medicine CDKN2A Genetics GNAS complex locus medicine Animals Humans Induced pluripotent stem cell 030304 developmental biology 0303 health sciences biology Pancreatic Ducts 01.06. Biológiai tudományok Cell Biology medicine.disease digestive system diseases 3. Good health Transplantation Organoids Pancreatic Neoplasms medicine.anatomical_structure Dysplasia Cdkn2a Gnas Ipmn Kras Pdac Disease Modelling Ductal Pancreatic Organoids Human Pluripotent Stem Cells In Vitro Differentiation Xenograft Mutation Cancer research biology.protein Molecular Medicine KRAS Carcinogenesis Pancreas 030217 neurology & neurosurgery Carcinoma Pancreatic Ductal |
| Zdroj: | Cell Stem Cell Cell Stem Cell 28, 1105-1124.e19 (2021) |
| ISSN: | 1934-5909 |
| DOI: | 10.1016/j.stem.2021.03.005 |
| Popis: | Personalized invitro 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 invitro. 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 invitro and invivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background. |
| Databáze: | OpenAIRE |
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