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TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells

Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high re...

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Detalles Bibliográficos
Autores principales: Liu, Jun, Akanuma, Naoki, Liu, Chengyang, Naji, Ali, Halff, Glenn A., Washburn, William K., Sun, Luzhe, Wang, Pei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971483/
https://www.ncbi.nlm.nih.gov/pubmed/27485764
http://dx.doi.org/10.1038/srep30904
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author Liu, Jun
Akanuma, Naoki
Liu, Chengyang
Naji, Ali
Halff, Glenn A.
Washburn, William K.
Sun, Luzhe
Wang, Pei
author_facet Liu, Jun
Akanuma, Naoki
Liu, Chengyang
Naji, Ali
Halff, Glenn A.
Washburn, William K.
Sun, Luzhe
Wang, Pei
author_sort Liu, Jun
collection PubMed
description Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
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spelling pubmed-49714832016-08-11 TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells Liu, Jun Akanuma, Naoki Liu, Chengyang Naji, Ali Halff, Glenn A. Washburn, William K. Sun, Luzhe Wang, Pei Sci Rep Article Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases. Nature Publishing Group 2016-08-03 /pmc/articles/PMC4971483/ /pubmed/27485764 http://dx.doi.org/10.1038/srep30904 Text en Copyright © 2016, 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
Liu, Jun
Akanuma, Naoki
Liu, Chengyang
Naji, Ali
Halff, Glenn A.
Washburn, William K.
Sun, Luzhe
Wang, Pei
TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title_full TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title_fullStr TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title_full_unstemmed TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title_short TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
title_sort tgf-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971483/
https://www.ncbi.nlm.nih.gov/pubmed/27485764
http://dx.doi.org/10.1038/srep30904
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