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

• Published in: Nature communications Vol. 8; no. 1; p. 14686
• Main Authors: Lee, Jonghyeob, Snyder, Emily R., Liu, Yinghua, Gu, Xueying, Wang, Jing, Flowers, Brittany M., Kim, Yoo Jung, Park, Sangbin, Szot, Gregory L., Hruban, Ralph H., Longacre, Teri A., Kim, Seung K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 14/63; 38/91; 42; 42/41; 42/70; 45; 631/67/1504/1713; 631/67/70; 64; Adenocarcinoma in Situ - genetics; Adult; Animals; Biomarkers, Tumor - metabolism; Carcinoma, Pancreatic Ductal - genetics; Cell Line; Cell Transplantation; Cloning; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Female; Genes; Humanities and Social Sciences; Humans; Male; Mice; Middle Aged; multidisciplinary; Mutation; Neuropeptides - metabolism; Pancreatic cancer; Pancreatic Ducts - cytology; Pancreatic Ducts - metabolism; Pancreatic Neoplasms - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Science; Science (multidisciplinary); Smad4 Protein - genetics; Spheres; Transcriptome; Tumor Suppressor Protein p53 - genetics; Viruses; United States > US; San Francisco California; California
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14686

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. Models of human pancreatic intraepithelial neoplasia (PanIN) development do not exist. Here, the authors induce oncogenic KRAS and mutations in CDKN2A , SMAD4 and TP53 in primary human pancreatic cells to generate a PanIN model that recapitulates molecular and pathologic features of native PanINs.