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

Author

Listed:
  • Andreia V. Pinho

    (The Garvan Institute of Medical Research
    Macquarie University
    Australian Pancreatic Cancer Genome Initiative (APGI))

  • Mathias Bulck

    (Vrije Universiteit Brussel)

  • Lorraine Chantrill

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI)
    St. Vincent’s Clinical School, UNSW)

  • Mehreen Arshi

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI))

  • Tatyana Sklyarova

    (Vrije Universiteit Brussel)

  • David Herrmann

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI)
    St. Vincent’s Clinical School, UNSW)

  • Claire Vennin

    (The Garvan Institute of Medical Research)

  • David Gallego-Ortega

    (The Garvan Institute of Medical Research
    St. Vincent’s Clinical School, UNSW)

  • Amanda Mawson

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI))

  • Marc Giry-Laterriere

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI))

  • 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
    Australian Pancreatic Cancer Genome Initiative (APGI)
    University of Sydney)

  • Phoebe Phillips

    (University of New South Wales)

  • Paul Timpson

    (The Garvan Institute of Medical Research
    Australian Pancreatic Cancer Genome Initiative (APGI)
    St. Vincent’s Clinical School, UNSW)

  • Andrew V. Biankin

    (Australian Pancreatic Cancer Genome Initiative (APGI)
    University of Glasgow
    Glasgow Royal Infirmary
    South Western Sydney Clinical School, UNSW)

  • Jianmin Wu

    (Australian Pancreatic Cancer Genome Initiative (APGI)
    Peking University Cancer Hospital & Institute)

  • Ilse Rooman

    (Australian Pancreatic Cancer Genome Initiative (APGI)
    Vrije Universiteit Brussel)

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.

Suggested Citation

  • Andreia V. Pinho & Mathias Bulck & Lorraine Chantrill & Mehreen Arshi & Tatyana Sklyarova & David Herrmann & Claire Vennin & David Gallego-Ortega & Amanda Mawson & Marc Giry-Laterriere & Astrid Magena, 2018. "ROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07497-z
    DOI: 10.1038/s41467-018-07497-z
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