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

被引：77

作者：

Breunig, Markus ^{[1
]}

Merkle, Jessica ^{[1
]}

Wagner, Martin ^{[1
]}

Melzer, Michael K. ^{[1
,2
]}

Barth, Thomas F. E. ^{[3
]}

Engleitner, Thomas ^{[4
,5
]}

Krumm, Johannes ^{[6
]}

Wiedenmann, Sandra ^{[1
,7
]}

Cohrs, Christian M. ^{[8
,9
,10
]}

Perkhofer, Lukas ^{[1
]}

Jain, Gaurav ^{[4
,5
]}

Kruger, Jana ^{[1
]}

Hermann, Patrick C. ^{[1
]}

Schmid, Maximilian ^{[1
]}

Madacsy, Tamara ^{[11
,12
]}

Varga, Arpad ^{[11
,12
]}

Griger, Joscha ^{[4
,5
]}

Azoitei, Ninel ^{[1
]}

Mueller, Martin ^{[1
]}

Wessely, Oliver ^{[13
]}

Robey, Pamela G. ^{[14
]}

Heller, Sandra ^{[1
]}

Dantes, Zahra ^{[15
]}

Reichert, Maximilian ^{[15
]}

Guenes, Cagatay ^{[2
]}

Bolenz, Christian ^{[2
]}

Kuhn, Florian ^{[1
]}

Maleth, Jozsef ^{[11
,12
,16
]}

Speier, Stephan ^{[8
,9
,10
]}

Liebau, Stefan ^{[17
]}

Sipos, Bence ^{[18
]}

Kuster, Bernhard ^{[6
,19
]}

Seufferlein, Thomas ^{[1
]}

Rad, Roland ^{[4
,5
]}

Meier, Matthias ^{[7
]}

Hohwieler, Meike ^{[1
]}

Kleger, Alexander ^{[1
]}

机构：

[1] Ulm Univ Hosp, Dept Internal Med 1, Ulm, Germany

[2] Ulm Univ, Dept Urol, Ulm, Germany

[3] Ulm Univ, Inst Pathol, Ulm, Germany

[4] Tech Univ Munich, Inst Mol Oncol & Funct Genom, Ctr Translat Canc Res, Sch Med, Munich, Germany

[5] Tech Univ Munich, Sch Med, Dept Med 2, Munich, Germany

[6] Tech Univ Munich, Chair Prote & Bioanalyt, Freising Weihenstephan, Germany

[7] Helmholtz Zentrum Munchen, Helmholtz Pioneer Campus, Neuherberg, Germany

[8] Tech Univ Dresden, Helmholtz Zentrum Munchen, Univ Clin Carl Gustav Carus, Paul Langerhans Inst Dresden PLID, Neuherberg, Germany

[9] Tech Univ Dresden, Fac Med, Inst Physiol, Dresden, Germany

[10] German Ctr Diabet Res DZD, Neuherberg, Germany

[11] Univ Szeged, Dept Internal Med 1, Szeged, Hungary

[12] Univ Szeged, MTA SZTE Momentum Epithelial Cell Signalling & Se, Szeged, Hungary

[13] Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH 44195 USA

[14] US Dept HHS, Skeletal Biol Sect, Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA

[15] Tech Univ Munich, Med Clin & Polyclin 2, Klinikum Rechts Isar, Munich, Germany

[16] Univ Szeged, SZTE Mol Gastroenterol Res Grp, HCEMM, Szeged, Hungary

[17] Eberhard Karls Univ Tubingen, Inst Neuroanat & Dev Biol INDB, Tubingen, Germany

[18] Univ Hosp Tubingen, Dept Internal Med 8, Tubingen, Germany

[19] Tech Univ Munich, Bavarian Biomol Mass Spectrometry Ctr BayBioMS, Freising Weihenstephan, Germany

来源：

CELL STEM CELL | 2021年 / 28卷 / 06期

基金：

欧洲研究理事会;

关键词：

ONCOGENE-INDUCED SENESCENCE; CELLULAR SENESCENCE; DISTINCT TUMOR; EXPRESSION; MOUSE; EMT; DIFFERENTIATION; TRANSPLANTATION; PROGENITORS; SUPPRESSION;

D O I：

10.1016/j.stem.2021.03.005

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 aMcCune-Albright patient. Each oncogene causes a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone formheterogenous 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.

引用

页码：1105 / +

页数：39

共 126 条

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