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

doi:10.1038/s41467-018-07497-z

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 (Pdx1^Cre;Robo2^F/F) show increased activation of Robo1⁺ myofibroblasts and induction of TGF-β and Wnt pathways. During pancreatitis, Pdx1^Cre;Robo2^F/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. ROBO2^low;ROBO1^high 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.

Original language	English
Article number	5083
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07497-z
Publication status	Published - 1 Dec 2018

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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.

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Pinho, A. V., 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, A. J., Phillips, P., Timpson, P., Biankin, A. V., Wu, J., & Rooman, I. (2018). ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling. Nature Communications, 9(1), 1-14. Article 5083. https://doi.org/10.1038/s41467-018-07497-z

@article{34c11258a76f4a3d876ec1a15fb44886,

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

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.",

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

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.",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07497-z",

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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

TY - JOUR

T1 - ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling

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

N1 - 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.

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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85057577578

U2 - 10.1038/s41467-018-07497-z

DO - 10.1038/s41467-018-07497-z

M3 - Article

C2 - 30504844

AN - SCOPUS:85057577578

SN - 2041-1723

VL - 9

SP - 1

EP - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5083

ER -

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

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