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

Nat Commun. 2018 Nov 30;9(1):5083. doi: 10.1038/s41467-018-07497-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • In Situ Hybridization
  • In Vitro Techniques
  • Male
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Pancreas / metabolism*
  • Pancreas / pathology*
  • Pancreatitis / genetics
  • Pancreatitis / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism*

Substances

  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Receptors, Immunologic
  • Robo2 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • pancreatic and duodenal homeobox 1 protein
  • roundabout protein