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SOX9 regulates ERBB signalling in pancreatic cancer development
  1. Adrien Grimont1,
  2. Andreia V Pinho2,3,
  3. Mark J Cowley2,3,
  4. Cécile Augereau1,
  5. Amanda Mawson2,3,
  6. Marc Giry-Laterrière2,3,
  7. Géraldine Van den Steen1,
  8. Nicola Waddell3,4,
  9. Marina Pajic2,3,5,
  10. Christine Sempoux6,
  11. Jianmin Wu2,3,5,
  12. Sean M Grimmond3,4,7,
  13. Andrew V Biankin2,3,5,7,
  14. Frédéric P Lemaigre1,
  15. Ilse Rooman2,3,5,
  16. Patrick Jacquemin1
  1. 1Université catholique de Louvain, de Duve Institute, Brussels, Belgium
  2. 2Cancer Research Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
  3. 3Australian Pancreatic Cancer Genome Initiative
  4. 4Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia
  5. 5St Vincent's Clinical School, University New South Wales, Australia
  6. 6Department of Pathology, Université catholique de Louvain, Cliniques Universitaires St Luc, Brussels, Belgium
  7. 7Wolfson Wohl Cancer Centre, University of Glasgow, Scotland, UK
  1. Correspondence to Dr Ilse Rooman, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, NSW 2010 Darlinghurst, Sydney, Australia; i.rooman@garvan.org.au; and, Dr Patrick Jacquemin, Université catholique de Louvain, de Duve Institute, Avenue Hippocrate 75/B1.75.03, Brussels B-1200, Belgium; patrick.jacquemin{at}uclouvain.be.

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.

  • IMMUNOHISTOCHEMISTRY
  • DEVELOPMENT GENES
  • EPIDERMAL GROWTH FACTOR
  • GENE TARGETING
  • PANCREATIC CANCER

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