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 - http://www.scopus.com/inward/record.url?scp=85057577578&partnerID=8YFLogxK
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 -