SOX9 regulates ERBB signalling in pancreatic cancer development

Adrien Grimont, Andreia V. Pinho, Mark J. Cowley, Cécile Augereau, Amanda Mawson, Marc Giry-Laterrière, Géraldine Van Den Steen, Nicola Waddell, Marina Pajic, Christine Sempoux, Jianmin Wu, Sean M. Grimmond, Andrew V. Biankin, Frédéric P. Lemaigre, Ilse Rooman, Patrick Jacquemin

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages1790-1799
Number of pages10
JournalGut
Volume64
Issue number11
DOIs
Publication statusPublished - 1 Nov 2015
Externally publishedYes

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Pancreatic Neoplasms
Adenocarcinoma
Cell Line
SOX9 Transcription Factor
Gene Expression
Metaplasia
Epidermal Growth Factor Receptor
Heterografts
Neoplasms
Therapeutics

Cite this

Grimont, A., Pinho, A. V., Cowley, M. J., Augereau, C., Mawson, A., Giry-Laterrière, M., ... Jacquemin, P. (2015). SOX9 regulates ERBB signalling in pancreatic cancer development. Gut, 64(11), 1790-1799. https://doi.org/10.1136/gutjnl-2014-307075
Grimont, Adrien ; Pinho, Andreia V. ; Cowley, Mark J. ; Augereau, Cécile ; Mawson, Amanda ; Giry-Laterrière, Marc ; Van Den Steen, Géraldine ; Waddell, Nicola ; Pajic, Marina ; Sempoux, Christine ; Wu, Jianmin ; Grimmond, Sean M. ; Biankin, Andrew V. ; Lemaigre, Frédéric P. ; Rooman, Ilse ; Jacquemin, Patrick. / SOX9 regulates ERBB signalling in pancreatic cancer development. In: Gut. 2015 ; Vol. 64, No. 11. pp. 1790-1799.
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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.",
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Grimont, A, Pinho, AV, Cowley, MJ, Augereau, C, Mawson, A, Giry-Laterrière, M, Van Den Steen, G, Waddell, N, Pajic, M, Sempoux, C, Wu, J, Grimmond, SM, Biankin, AV, Lemaigre, FP, Rooman, I & Jacquemin, P 2015, 'SOX9 regulates ERBB signalling in pancreatic cancer development', Gut, vol. 64, no. 11, pp. 1790-1799. https://doi.org/10.1136/gutjnl-2014-307075

SOX9 regulates ERBB signalling in pancreatic cancer development. / Grimont, Adrien; Pinho, Andreia V.; Cowley, Mark J.; Augereau, Cécile; Mawson, Amanda; Giry-Laterrière, Marc; Van Den Steen, Géraldine; Waddell, Nicola; Pajic, Marina; Sempoux, Christine; Wu, Jianmin; Grimmond, Sean M.; Biankin, Andrew V.; Lemaigre, Frédéric P.; Rooman, Ilse; Jacquemin, Patrick.

In: Gut, Vol. 64, No. 11, 01.11.2015, p. 1790-1799.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Grimont, Adrien

AU - Pinho, Andreia V.

AU - Cowley, Mark J.

AU - Augereau, Cécile

AU - Mawson, Amanda

AU - Giry-Laterrière, Marc

AU - Van Den Steen, Géraldine

AU - Waddell, Nicola

AU - Pajic, Marina

AU - Sempoux, Christine

AU - Wu, Jianmin

AU - Grimmond, Sean M.

AU - Biankin, Andrew V.

AU - Lemaigre, Frédéric P.

AU - Rooman, Ilse

AU - Jacquemin, Patrick

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N2 - 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.

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Grimont A, Pinho AV, Cowley MJ, Augereau C, Mawson A, Giry-Laterrière M et al. SOX9 regulates ERBB signalling in pancreatic cancer development. Gut. 2015 Nov 1;64(11):1790-1799. https://doi.org/10.1136/gutjnl-2014-307075