Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

Jonghyeob Lee, Emily R. Snyder, Yinghua Liu, Xueying Gu, Jing Wang, Brittany M. Flowers, Yoo Jung Kim, Sangbin Park, Gregory L. Szot, Ralph H. Hruban, Teri A. Longacre and Seung K. Kim ()
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Jonghyeob Lee: Stanford University School of Medicine
Emily R. Snyder: Stanford University School of Medicine
Yinghua Liu: Stanford University School of Medicine
Xueying Gu: Stanford University School of Medicine
Jing Wang: Stanford University School of Medicine
Brittany M. Flowers: Stanford University School of Medicine
Yoo Jung Kim: Stanford University School of Medicine
Sangbin Park: Stanford University School of Medicine
Gregory L. Szot: UCSF Transplantation Surgery, University of California, San Francisco
Ralph H. Hruban: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine
Teri A. Longacre: Stanford University School of Medicine
Seung K. Kim: Stanford University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14686

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