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

Andreia V Pinho1,2,3, Mathias Van Bulck4, Lorraine Chantrill5,6,7

  • 1Cancer Division, The Garvan Institute of Medical Research, Sydney, Darlinghurst 2010, NSW, Australia. andreia.pinho@mq.edu.au.

Nature Communications
|December 4, 2018
PubMed

Insights

Loss of epithelial Robo2 in pancreatic cancer promotes stromal activation and poor survival. Restoring Robo2 function may suppress pancreatic ductal adenocarcinoma progression by targeting stromal and immune responses.

Area of Science:

  • Oncology
  • Cell Biology
  • Immunology

Background:

  • Genomic aberrations in the SLIT-ROBO pathway are common in pancreatic ductal adenocarcinoma (PDAC).
  • The specific role of the SLIT-ROBO pathway in pancreatic stroma and cancer progression remains largely undefined.

Purpose of the Study:

  • To investigate the functional role of Robo1 and Robo2 in pancreatic pancreatitis and PDAC.
  • To determine the impact of epithelial Robo2 loss on stromal activation and immune infiltration in PDAC.
  • To evaluate the therapeutic potential of targeting the SLIT-ROBO pathway in PDAC.

Main Methods:

  • Utilized Pdx1Cre;Robo2F/F mouse models for pancreatitis and PDAC.
  • Performed cell culture experiments to assess myofibroblast activation and pathway induction.
  • Analyzed tissue samples from PDAC patients for ROBO1 and ROBO2 expression.
  • Administered the TGF-β inhibitor galunisertib in mouse models.

Main Results:

  • Epithelial Robo2 loss in mice led to increased myofibroblast activation, collagen deposition, and T-cell infiltration.
  • Robo1 expression was prominent in the stroma of PDAC mice and patients.
  • PDAC patients with low ROBO2 and high ROBO1 expression exhibited significantly poorer survival.
  • Galunisertib treatment reversed pancreatitis-associated stromal and immune changes.

Conclusions:

  • Robo2 functions as a non-autonomous stroma suppressor gene by inhibiting myofibroblast activation and T-cell infiltration.
  • ROBO1/2 expression patterns in PDAC patients may predict survival outcomes.
  • Targeting ROBO1/2 signaling, potentially via TGF-β inhibitors, could offer novel therapeutic strategies for PDAC by modulating the tumor stroma and immune microenvironment.

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