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

Markus Breunig, Jessica Merkle, Martin Wagner, Michael K. Melzer, Thomas F.E. Barth, Thomas Engleitner, Johannes Krumm, Sandra Wiedenmann, Christian M. Cohrs, Lukas Perkhofer, Gaurav Jain, Jana Krüger, Patrick C. Hermann, Maximilian Schmid, Tamara Madácsy, Árpád Varga, Joscha Griger, Ninel Azoitei, Martin Müller, Oliver WesselyPamela G. Robey, Sandra Heller, Zahra Dantes, Maximilian Reichert, Cagatay Günes, Christian Bolenz, Florian Kuhn, József Maléth, Stephan Speier, Stefan Liebau, Bence Sipos, Bernhard Kuster, Thomas Seufferlein, Roland Rad, Matthias Meier, Meike Hohwieler, Alexander Kleger

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1105-1124.e19
JournalCell Stem Cell
Volume28
Issue number6
DOIs
StatePublished - 3 Jun 2021

Keywords

  • CDKN2A
  • GNAS
  • IPMN
  • KRAS
  • PDAC
  • disease modelling
  • ductal pancreatic organoids
  • human pluripotent stem cells
  • in vitro differentiation
  • xenograft

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