title: SOX9 regulates ERBB signalling in pancreatic cancer development.
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.
  
  
  METHODS
  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.
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Adrien
authors.initials: A
authors.lastname: Grimont
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative.
authors.forename: Andreia V
authors.initials: AV
authors.lastname: Pinho
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Cécile
authors.initials: C
authors.lastname: Augereau
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mawson
authors.affiliation: Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia Australian Pancreatic Cancer Genome Initiative.
authors.forename: Marc
authors.initials: M
authors.lastname: Giry-Laterrière
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Van den Steen
authors.affiliation: Australian Pancreatic Cancer Genome Initiative Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Pajic
authors.affiliation: Department of Pathology, Université catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.affiliation: 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.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: 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.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
authors.affiliation: 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.
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.affiliation: Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000235:genetics; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: DEVELOPMENT GENES; EPIDERMAL GROWTH FACTOR; GENE TARGETING; IMMUNOHISTOCHEMISTRY; PANCREATIC CANCER