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

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

Author information

1
Cancer Division, The Garvan Institute of Medical Research, Sydney, Darlinghurst 2010, NSW, Australia. andreia.pinho@mq.edu.au.
2
Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Macquarie University 2109, NSW, Australia. andreia.pinho@mq.edu.au.
3
Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia. andreia.pinho@mq.edu.au.
4
Oncology Research Centre, Vrije Universiteit Brussel, Brussels, 1090, Belgium.
5
Cancer Division, The Garvan Institute of Medical Research, Sydney, Darlinghurst 2010, NSW, Australia.
6
Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia.
7
St. Vincent's Clinical School, UNSW, Sydney, Darlinghurst 2010, NSW, Australia.
8
Beta cell Neogenesis Lab, Vrije Universiteit Brussel, Brussels, 1090, Belgium.
9
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, St. Leonards 2065, NSW, Australia.
10
Lowy Cancer Research Centre, University of New South Wales, Sydney, Sydney 2052, NSW, Australia.
11
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, Scotland, UK.
12
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G5 0SF, Scotland, UK.
13
South Western Sydney Clinical School, UNSW, Liverpool, Liverpool 2170, NSW, Australia.
14
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Cancer Bioinformatics, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
15
Australian Pancreatic Cancer Genome Initiative (APGI), Sydney, Darlinghurst 2010, NSW, Australia. irooman@vub.be.
16
Oncology Research Centre, Vrije Universiteit Brussel, Brussels, 1090, Belgium. irooman@vub.be.

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.

PMID:
30504844
PMCID:
PMC6269509
DOI:
10.1038/s41467-018-07497-z
[Indexed for MEDLINE]
Free PMC Article

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