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.
Highlights
Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear
Analyzing whole-tissue gene expression, we previously showed a progressive loss of Robo[2], a progressive increase in Robo[1] and no change in Robo[3] mRNA expression when sequentially comparing normal mouse pancreas, models of acinar-to-ductal metaplasia and a genetically engineered mouse model of PDAC5
Further to a role in axonal guidance, the SLIT–ROBO pathway has been implicated in cancer[4], with studies showing that Slit[2] and Robo[1] regulate tumour cell migration and invasion through regulation of the β-catenin/Wnt pathway[11,20,21,22] and affect neural remodelling in pancreatic cancer[11,12]
Summary
Whereas genomic aberrations in the SLIT-ROBO pathway are frequent in pancreatic ductal adenocarcinoma (PDAC), their function in the pancreas is unclear. Cell cultures of mice with loss of epithelial Robo[2] (Pdx1Cre;Robo2F/F) show increased activation of Robo1+ myofibroblasts and induction of TGF-β and Wnt pathways. Chronic pancreatitis is a major risk factor for the development of PDAC Both diseases share a common aetiology in the exocrine pancreatic tissue and are characterised by a strong desmoplastic response, comprised of multiple stromal cell types, including activated myofibroblasts or stellate cells and immune cell infiltrates[2,3]. We describe cell-type-specific changes in Robo and Slit gene expression during pancreatitis and tumour development, and we reveal their functional consequence in reshaping the tissue’s constituents. Loss of Robo[2] signalling in the exocrine epithelium reprograms the microenvironment, resulting in the prominent activation of myofibroblasts and increased T-cell infiltration, with a critical role for transforming growth factor beta (TGF-β) signalling. Our results provide insights into the mechanisms of the desmoplastic response characteristic of exocrine pancreatic pathologies, which is the subject of investigation in clinical trials
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