Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression

Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression

Summary: The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of...

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Main Authors: Rute M.M. Ferreira, Rocio Sancho, Hendrik A. Messal, Emma Nye, Bradley Spencer-Dene, Richard K. Stone, Gordon Stamp, Ian Rosewell, Alberto Quaglia, Axel Behrens
Format: Article
Language:English
Published: Elsevier 2017-10-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124717314134
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spelling doaj-6fdd133864f14223b3c2f5abfdfe61192020-11-24T22:01:14ZengElsevierCell Reports2211-12472017-10-01214966978Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker ExpressionRute M.M. Ferreira0Rocio Sancho1Hendrik A. Messal2Emma Nye3Bradley Spencer-Dene4Richard K. Stone5Gordon Stamp6Ian Rosewell7Alberto Quaglia8Axel Behrens9Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKAdult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKAdult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKExperimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKExperimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKExperimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKExperimental Histopathology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKTransgenic Service–Biological Research Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKKing’s College Hospital/King’s College London, Institute of Liver Studies, Denmark Hill, London SE5 9RS, UKAdult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; King’s College London, Faculty of Life Sciences and Medicine, Guy’s Campus, London SE1 1UL, UK; Corresponding authorSummary: The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. : Pancreatic intraepithelial neoplasias (PanINs) are established precursor lesions to pancreatic ductal adenocarcinoma (PDAC). Ferreira et al. show that this model represents acinar-derived PDAC and that, in contrast, duct-derived PDAC does not develop via PanINs. PanIN-like lesions occurring alongside duct-derived tumors arise from adjacent non-mutant tissue and do not represent tumor precursors. Keywords: PDAC, pancreatic cancer, mouse models, progression, PanINs, AGR2, cell of originhttp://www.sciencedirect.com/science/article/pii/S2211124717314134
collection DOAJ
language English
format Article
sources DOAJ
author Rute M.M. Ferreira
Rocio Sancho
Hendrik A. Messal
Emma Nye
Bradley Spencer-Dene
Richard K. Stone
Gordon Stamp
Ian Rosewell
Alberto Quaglia
Axel Behrens
spellingShingle Rute M.M. Ferreira
Rocio Sancho
Hendrik A. Messal
Emma Nye
Bradley Spencer-Dene
Richard K. Stone
Gordon Stamp
Ian Rosewell
Alberto Quaglia
Axel Behrens
Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
Cell Reports
author_facet Rute M.M. Ferreira
Rocio Sancho
Hendrik A. Messal
Emma Nye
Bradley Spencer-Dene
Richard K. Stone
Gordon Stamp
Ian Rosewell
Alberto Quaglia
Axel Behrens
author_sort Rute M.M. Ferreira
title Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
title_short Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
title_full Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
title_fullStr Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
title_full_unstemmed Duct- and Acinar-Derived Pancreatic Ductal Adenocarcinomas Show Distinct Tumor Progression and Marker Expression
title_sort duct- and acinar-derived pancreatic ductal adenocarcinomas show distinct tumor progression and marker expression
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2017-10-01
description Summary: The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial. Here, we show that identical oncogenic drivers trigger PDAC originating from both ductal and acinar cells with similar histology but with distinct pathophysiology and marker expression dependent on cell of origin. Whereas acinar-derived tumors exhibited low AGR2 expression and were preceded by pancreatic intraepithelial neoplasias (PanINs), duct-derived tumors displayed high AGR2 and developed independently of a PanIN stage via non-mucinous lesions. Using orthotopic transplantation and chimera experiments, we demonstrate that PanIN-like lesions can be induced by PDAC as bystanders in adjacent healthy tissues, explaining the co-existence of mucinous and non-mucinous lesions and highlighting the need to distinguish between true precursor PanINs and PanIN-like bystander lesions. Our results suggest AGR2 as a tool to stratify PDAC according to cell of origin, highlight that not all PanIN-like lesions are precursors of PDAC, and add an alternative progression route to the current model of PDAC development. : Pancreatic intraepithelial neoplasias (PanINs) are established precursor lesions to pancreatic ductal adenocarcinoma (PDAC). Ferreira et al. show that this model represents acinar-derived PDAC and that, in contrast, duct-derived PDAC does not develop via PanINs. PanIN-like lesions occurring alongside duct-derived tumors arise from adjacent non-mutant tissue and do not represent tumor precursors. Keywords: PDAC, pancreatic cancer, mouse models, progression, PanINs, AGR2, cell of origin
url http://www.sciencedirect.com/science/article/pii/S2211124717314134
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