Adrien Grimont1, Andreia V Pinho2, Mark J Cowley2, Cécile Augereau1, Amanda Mawson2, Marc Giry-Laterrière2, Géraldine Van den Steen1, Nicola Waddell3, Marina Pajic4, Christine Sempoux5, Jianmin Wu4, Sean M Grimmond6, Andrew V Biankin7, Frédéric P Lemaigre1, Ilse Rooman4, Patrick Jacquemin1. 1. Université catholique de Louvain, de Duve Institute, Brussels, Belgium. 2. Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative. 3. Australian Pancreatic Cancer Genome Initiative Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia. 4. Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative St Vincent's Clinical School, University New South Wales, Australia. 5. Department of Pathology, Université catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium. 6. Australian Pancreatic Cancer Genome Initiative Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia Wolfson Wohl Cancer Centre, University of Glasgow, Scotland, UK. 7. Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative St Vincent's Clinical School, University New South Wales, Australia Wolfson Wohl Cancer Centre, University of Glasgow, Scotland, UK.
Abstract
OBJECTIVE: The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. DESIGN: We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. RESULTS: We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. CONCLUSIONS: By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. DESIGN: We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. RESULTS: We found genetic aberrations in the SOX9 gene in about 15% of patienttumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. CONCLUSIONS: By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
DEVELOPMENT GENES; EPIDERMAL GROWTH FACTOR; GENE TARGETING; IMMUNOHISTOCHEMISTRY; PANCREATIC CANCER
Authors: L G Kondratyeva; I P Chernov; M V Zinovyeva; V I Egorov; E P Kopantzev; E D Sverdlov Journal: Dokl Biochem Biophys Date: 2018-08-31 Impact factor: 0.788