Cargando…

A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of...

Descripción completa

Detalles Bibliográficos
Autores principales: Coleman, Orla, Henry, Michael, O’Neill, Fiona, Roche, Sandra, Swan, Niall, Boyle, Lorraine, Murphy, Jean, Meiller, Justine, Conlon, Neil T., Geoghegan, Justin, Conlon, Kevin C., Lynch, Vincent, Straubinger, Ninfa L., Straubinger, Robert M., McVey, Gerard, Moriarty, Michael, Meleady, Paula, Clynes, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313850/
https://www.ncbi.nlm.nih.gov/pubmed/30404163
http://dx.doi.org/10.3390/proteomes6040045
_version_ 1783384027207565312
author Coleman, Orla
Henry, Michael
O’Neill, Fiona
Roche, Sandra
Swan, Niall
Boyle, Lorraine
Murphy, Jean
Meiller, Justine
Conlon, Neil T.
Geoghegan, Justin
Conlon, Kevin C.
Lynch, Vincent
Straubinger, Ninfa L.
Straubinger, Robert M.
McVey, Gerard
Moriarty, Michael
Meleady, Paula
Clynes, Martin
author_facet Coleman, Orla
Henry, Michael
O’Neill, Fiona
Roche, Sandra
Swan, Niall
Boyle, Lorraine
Murphy, Jean
Meiller, Justine
Conlon, Neil T.
Geoghegan, Justin
Conlon, Kevin C.
Lynch, Vincent
Straubinger, Ninfa L.
Straubinger, Robert M.
McVey, Gerard
Moriarty, Michael
Meleady, Paula
Clynes, Martin
author_sort Coleman, Orla
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of resistance to conventional therapies are among the problems associated with management of the disease. A better understanding of pancreatic tumour biology and discovery of new potential therapeutic targets are important goals in pancreatic cancer research. This study describes the comparative quantitative LC-MS/MS proteomic analysis of the membrane-enriched proteome of 10 human pancreatic ductal adenocarcinomas, 9 matched adjacent-normal pancreas and patient-derived xenografts (PDXs) in mice (10 at F1 generation and 10 F2). Quantitative label-free LC-MS/MS data analysis identified 129 proteins upregulated, and 109 downregulated, in PDAC, compared to adjacent-normal tissue. In this study, analysing peptide MS/MS data from the xenografts, great care was taken to distinguish species-specific peptides definitively derived from human sequences, or from mice, which could not be distinguished. The human-only peptides from the PDXs are of particular value, since only human tumour cells survive, and stromal cells are replaced during engraftment in the mouse; this list is, therefore, enriched in tumour-associated proteins, some of which might be potential therapeutic or diagnostic targets. Using human-specific sequences, 32 proteins were found to be upregulated, and 113 downregulated in PDX F1 tumours, compared to primary PDAC. Differential expression of CD55 between PDAC and normal pancreas, and expression across PDX generations, was confirmed by Western blotting. These data indicate the value of using PDX models in PDAC research. This study is the first comparative proteomic analysis of PDAC which employs PDX models to identify patient tumour cell-associated proteins, in an effort to find robust targets for therapeutic treatment of PDAC.
format Online
Article
Text
id pubmed-6313850
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63138502019-01-07 A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts Coleman, Orla Henry, Michael O’Neill, Fiona Roche, Sandra Swan, Niall Boyle, Lorraine Murphy, Jean Meiller, Justine Conlon, Neil T. Geoghegan, Justin Conlon, Kevin C. Lynch, Vincent Straubinger, Ninfa L. Straubinger, Robert M. McVey, Gerard Moriarty, Michael Meleady, Paula Clynes, Martin Proteomes Article Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide; it develops in a relatively symptom-free manner, leading to rapid disease progression and metastasis, leading to a 5-year survival rate of less than 5%. A lack of dependable diagnostic markers and rapid development of resistance to conventional therapies are among the problems associated with management of the disease. A better understanding of pancreatic tumour biology and discovery of new potential therapeutic targets are important goals in pancreatic cancer research. This study describes the comparative quantitative LC-MS/MS proteomic analysis of the membrane-enriched proteome of 10 human pancreatic ductal adenocarcinomas, 9 matched adjacent-normal pancreas and patient-derived xenografts (PDXs) in mice (10 at F1 generation and 10 F2). Quantitative label-free LC-MS/MS data analysis identified 129 proteins upregulated, and 109 downregulated, in PDAC, compared to adjacent-normal tissue. In this study, analysing peptide MS/MS data from the xenografts, great care was taken to distinguish species-specific peptides definitively derived from human sequences, or from mice, which could not be distinguished. The human-only peptides from the PDXs are of particular value, since only human tumour cells survive, and stromal cells are replaced during engraftment in the mouse; this list is, therefore, enriched in tumour-associated proteins, some of which might be potential therapeutic or diagnostic targets. Using human-specific sequences, 32 proteins were found to be upregulated, and 113 downregulated in PDX F1 tumours, compared to primary PDAC. Differential expression of CD55 between PDAC and normal pancreas, and expression across PDX generations, was confirmed by Western blotting. These data indicate the value of using PDX models in PDAC research. This study is the first comparative proteomic analysis of PDAC which employs PDX models to identify patient tumour cell-associated proteins, in an effort to find robust targets for therapeutic treatment of PDAC. MDPI 2018-11-06 /pmc/articles/PMC6313850/ /pubmed/30404163 http://dx.doi.org/10.3390/proteomes6040045 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Coleman, Orla
Henry, Michael
O’Neill, Fiona
Roche, Sandra
Swan, Niall
Boyle, Lorraine
Murphy, Jean
Meiller, Justine
Conlon, Neil T.
Geoghegan, Justin
Conlon, Kevin C.
Lynch, Vincent
Straubinger, Ninfa L.
Straubinger, Robert M.
McVey, Gerard
Moriarty, Michael
Meleady, Paula
Clynes, Martin
A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title_full A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title_fullStr A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title_full_unstemmed A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title_short A Comparative Quantitative LC-MS/MS Profiling Analysis of Human Pancreatic Adenocarcinoma, Adjacent-Normal Tissue, and Patient-Derived Tumour Xenografts
title_sort comparative quantitative lc-ms/ms profiling analysis of human pancreatic adenocarcinoma, adjacent-normal tissue, and patient-derived tumour xenografts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313850/
https://www.ncbi.nlm.nih.gov/pubmed/30404163
http://dx.doi.org/10.3390/proteomes6040045
work_keys_str_mv AT colemanorla acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT henrymichael acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT oneillfiona acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT rochesandra acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT swanniall acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT boylelorraine acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT murphyjean acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT meillerjustine acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT conlonneilt acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT geogheganjustin acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT conlonkevinc acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT lynchvincent acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT straubingerninfal acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT straubingerrobertm acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT mcveygerard acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT moriartymichael acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT meleadypaula acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT clynesmartin acomparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT colemanorla comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT henrymichael comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT oneillfiona comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT rochesandra comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT swanniall comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT boylelorraine comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT murphyjean comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT meillerjustine comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT conlonneilt comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT geogheganjustin comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT conlonkevinc comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT lynchvincent comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT straubingerninfal comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT straubingerrobertm comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT mcveygerard comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT moriartymichael comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT meleadypaula comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts
AT clynesmartin comparativequantitativelcmsmsprofilinganalysisofhumanpancreaticadenocarcinomaadjacentnormaltissueandpatientderivedtumourxenografts