Modelling Plasticity and Dysplasia of Pancreatic Ductal Organoids Derived from Human Pluripotent Stem Cells

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 present a differentiation matrix to generate pancreatic duct-like organoids (PDLOs) from hPSCs. PDLOs showed morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, and matured upon transplantation into mice. PDLOs were generated from hPSCs inducibly expressing oncogenic GNAS, KRAS, or KRAS with genetic covariance of mutated CDKN2A, and from McCune-Albright as well as familial pancreatic cancer patients. Each oncogene caused a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone or KRAS with CDKN2A-loss developed well- or dedifferentiated pancreatic ductal adenocarcinomas, PDLOs with mutant GNAS led to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation in a genetically defined background.