ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling

Andreia V. Pinho, Mathias Van Bulck, Lorraine Chantrill, Mehreen Arshi, Tatyana Sklyarova, David Herrmann, Claire Vennin, David Gallego-Ortega, Amanda Mawson, Marc Giry-Laterriere, Astrid Magenau, Gunther Leuckx, Luc Baeyens, Anthony J. Gill, Phoebe Phillips, Paul Timpson, Andrew V. Biankin, Jianmin Wu, Ilse Rooman

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.

LanguageEnglish
Article number5083
Pages1-14
Number of pages14
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

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Suppressor Genes
suppressors
pancreas
Transforming Growth Factor beta
genes
Myofibroblasts
Pancreas
Adenocarcinoma
T-cells
Genes
Chemical activation
LY-2157299
mice
Infiltration
activation
infiltration
Pancreatitis
inhibitors
Aberrations
T-Lymphocytes

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Pinho, A. V., Van Bulck, M., Chantrill, L., Arshi, M., Sklyarova, T., Herrmann, D., ... Rooman, I. (2018). ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. Nature Communications, 9(1), 1-14. [5083]. https://doi.org/10.1038/s41467-018-07497-z
Pinho, Andreia V. ; Van Bulck, Mathias ; Chantrill, Lorraine ; Arshi, Mehreen ; Sklyarova, Tatyana ; Herrmann, David ; Vennin, Claire ; Gallego-Ortega, David ; Mawson, Amanda ; Giry-Laterriere, Marc ; Magenau, Astrid ; Leuckx, Gunther ; Baeyens, Luc ; Gill, Anthony J. ; Phillips, Phoebe ; Timpson, Paul ; Biankin, Andrew V. ; Wu, Jianmin ; Rooman, Ilse. / ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 1-14.
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abstract = "Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.",
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Pinho, AV, Van Bulck, M, Chantrill, L, Arshi, M, Sklyarova, T, Herrmann, D, Vennin, C, Gallego-Ortega, D, Mawson, A, Giry-Laterriere, M, Magenau, A, Leuckx, G, Baeyens, L, Gill, AJ, Phillips, P, Timpson, P, Biankin, AV, Wu, J & Rooman, I 2018, 'ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling', Nature Communications, vol. 9, no. 1, 5083, pp. 1-14. https://doi.org/10.1038/s41467-018-07497-z

ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. / Pinho, Andreia V.; Van Bulck, Mathias; Chantrill, Lorraine; Arshi, Mehreen; Sklyarova, Tatyana; Herrmann, David; Vennin, Claire; Gallego-Ortega, David; Mawson, Amanda; Giry-Laterriere, Marc; Magenau, Astrid; Leuckx, Gunther; Baeyens, Luc; Gill, Anthony J.; Phillips, Phoebe; Timpson, Paul; Biankin, Andrew V.; Wu, Jianmin; Rooman, Ilse.

In: Nature Communications, Vol. 9, No. 1, 5083, 01.12.2018, p. 1-14.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pinho, Andreia V.

AU - Van Bulck, Mathias

AU - Chantrill, Lorraine

AU - Arshi, Mehreen

AU - Sklyarova, Tatyana

AU - Herrmann, David

AU - Vennin, Claire

AU - Gallego-Ortega, David

AU - Mawson, Amanda

AU - Giry-Laterriere, Marc

AU - Magenau, Astrid

AU - Leuckx, Gunther

AU - Baeyens, Luc

AU - Gill, Anthony J.

AU - Phillips, Phoebe

AU - Timpson, Paul

AU - Biankin, Andrew V.

AU - Wu, Jianmin

AU - Rooman, Ilse

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PY - 2018/12/1

Y1 - 2018/12/1

N2 - Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Here we report that in pancreatitis and PDAC mouse models, epithelial Robo2 expression is lost while Robo1 expression becomes most prominent in the stroma. Cell cultures of mice with loss of epithelial Robo2 (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1Cre;Robo2F/F mice present enhanced myofibroblast activation, collagen crosslinking, T-cell infiltration and tumorigenic immune markers. The TGF-β inhibitor galunisertib suppresses these effects. In PDAC patients, ROBO2 expression is overall low while ROBO1 is variably expressed in epithelium and high in stroma. ROBO2low;ROBO1high patients present the poorest survival. In conclusion, Robo2 acts non-autonomously as a stroma suppressor gene by restraining myofibroblast activation and T-cell infiltration. ROBO1/2 expression in PDAC patients may guide therapy with TGF-β inhibitors or other stroma /immune modulating agents.

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