title: Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells.
abstract: Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Jonghyeob
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Snyder
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Brittany M
authors.initials: BM
authors.lastname: Flowers
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Yoo Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Sangbin
authors.initials: S
authors.lastname: Park
authors.affiliation: UCSF Transplantation Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Szot
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B300, Stanford, California 94305, USA.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D065311:Adenocarcinoma in Situ / Q000235:genetics*; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D002460:Cell Line; D017690:Cell Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C117307:KRAS protein, human; D009479:Neuropeptides; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C056900:neuromedin U; D016283:Proto-Oncogene Proteins p21(ras)