Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.
CDKN2A
GNAS
IPMN
KRAS
PDAC
disease modelling
ductal pancreatic organoids
human pluripotent stem cells
in vitro differentiation
xenograft
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
03 06 2021
03 06 2021
Historique:
received:
01
05
2020
revised:
22
12
2020
accepted:
09
03
2021
pubmed:
30
4
2021
medline:
25
6
2021
entrez:
29
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33915078
pii: S1934-5909(21)00111-9
doi: 10.1016/j.stem.2021.03.005
pmc: PMC8461636
mid: NIHMS1733722
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1105-1124.e19Subventions
Organisme : NIDDK NIH HHS
ID : UH3 DK107357
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA DE000380
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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