RT Journal Article
SR Electronic
T1 SOX9 regulates ERBB signalling in pancreatic cancer development
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1790
OP 1799
DO 10.1136/gutjnl-2014-307075
VO 64
IS 11
A1 Grimont, Adrien
A1 Pinho, Andreia V
A1 Cowley, Mark J
A1 Augereau, Cécile
A1 Mawson, Amanda
A1 Giry-Laterrière, Marc
A1 Van den Steen, Géraldine
A1 Waddell, Nicola
A1 Pajic, Marina
A1 Sempoux, Christine
A1 Wu, Jianmin
A1 Grimmond, Sean M
A1 Biankin, Andrew V
A1 Lemaigre, Frédéric P
A1 Rooman, Ilse
A1 Jacquemin, Patrick
YR 2015
UL http://gut.bmj.com/content/64/11/1790.abstract
AB 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.