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

Andreia V. Pinho (), Mathias 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 and Ilse Rooman ()
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Andreia V. Pinho: The Garvan Institute of Medical Research
Mathias Bulck: Vrije Universiteit Brussel
Lorraine Chantrill: The Garvan Institute of Medical Research
Mehreen Arshi: The Garvan Institute of Medical Research
Tatyana Sklyarova: Vrije Universiteit Brussel
David Herrmann: The Garvan Institute of Medical Research
Claire Vennin: The Garvan Institute of Medical Research
David Gallego-Ortega: The Garvan Institute of Medical Research
Amanda Mawson: The Garvan Institute of Medical Research
Marc Giry-Laterriere: The Garvan Institute of Medical Research
Astrid Magenau: The Garvan Institute of Medical Research
Gunther Leuckx: Vrije Universiteit Brussel
Luc Baeyens: Vrije Universiteit Brussel
Anthony J. Gill: The Garvan Institute of Medical Research
Phoebe Phillips: University of New South Wales
Paul Timpson: The Garvan Institute of Medical Research
Andrew V. Biankin: Australian Pancreatic Cancer Genome Initiative (APGI)
Jianmin Wu: Australian Pancreatic Cancer Genome Initiative (APGI)
Ilse Rooman: Australian Pancreatic Cancer Genome Initiative (APGI)

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07497-z

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