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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Seung K. Kim, 2017. "Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14686
    DOI: 10.1038/ncomms14686
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    Cited by:

    1. Yi Xu & Michael H. Nipper & Angel A. Dominguez & Zhenqing Ye & Naoki Akanuma & Kevin Lopez & Janice J. Deng & Destiny Arenas & Ava Sanchez & Francis E. Sharkey & Colin M. Court & Aatur D. Singhi & Hua, 2024. "Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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