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Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344977/ https://www.ncbi.nlm.nih.gov/pubmed/28272465 http://dx.doi.org/10.1038/ncomms14686 |
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author | 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. |
author_facet | 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. |
author_sort | Lee, Jonghyeob |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5344977 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53449772017-03-21 Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells 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. Nat Commun Article 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. Nature Publishing Group 2017-03-08 /pmc/articles/PMC5344977/ /pubmed/28272465 http://dx.doi.org/10.1038/ncomms14686 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article 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. Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title | Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title_full | Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title_fullStr | Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title_full_unstemmed | Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title_short | Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
title_sort | reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344977/ https://www.ncbi.nlm.nih.gov/pubmed/28272465 http://dx.doi.org/10.1038/ncomms14686 |
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