Grimont, A. et al. (2014) SOX9 regulates ERBB signalling in pancreatic cancer development. Gut, 64(11), pp. 1790-1799. (doi: 10.1136/gutjnl-2014-307075) (PMID:25336113)
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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.
| Item Type: | Articles |
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| Additional Information: | This work was supported by grants from the Cancer Institute NSW; National Health and Medical Research Council of Australia; Australian Government: Department of Innovation, Industry, Science, Research and Tertiary Education; Australian Cancer Research Foundation; Queensland Government; University of Queensland; Cancer Council NSW; Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; R.T. Hall Trust; Petre Foundation; Jane Hemstritch in memory of Philip Hemstritch; Gastroenterological Society of Australia; American Association for Cancer Research Landon Foundation—INNOVATOR Award; Royal Australasian College of Surgeons; Royal Australasian College of Physicians; Royal College of Pathologists of Australasia; HGSC-BCM: NHGRI U54 HG003273; CPRIT grant RP101353-P7 (Tumour Banking for Genomic Research and Clinical Translation Site 1); Fondation contre le Cancer (Belgium); Fonds de la Recherche Scientifique-FNRS (Belgium); Université catholique de Louvain. AG was supported by a grant from EU FP7 (Marie Curie Initial Training Network BOLD) and a Télévie fellowship. AVP and MJC are supported by early career fellowships from Cancer Institute NSW. CA holds a Télévie fellowship, IR is a Future Research Fellow of the Cancer Institute NSW (10/FRL2-03) and PJ is a Research Associate of the Fonds de la Recherche Scientifique-FNRS. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Biankin, Professor Andrew and Grimmond, Professor Sean |
| Authors: | Grimont, A., Pinho, A. V., Cowley, M. J., Augereau, C., Mawson, A., Giry-Laterrière, M., Van den Steen, G., Waddell, N., Pajic, M., Sempoux, C., Wu, J., Grimmond, S. M., Biankin, A. V., Lemaigre, F. P., Rooman, I., and Jacquemin, P. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Gut |
| Publisher: | BMJ Publishing Group |
| ISSN: | 0017-5749 |
| ISSN (Online): | 1468-3288 |
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