Snail cooperates with Kras G12D in vivo to increase stem cell factor and enhance mast cell infiltration.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced fibro-inflammatory stromal reaction that contributes to tumor progression. A critical step in invasion and metastasis is the epithelial-to-mesenchymal transition (EMT), which can be regulated by the Snail family of transcription factors. Overexpression of Snail (Snai1) and mutant Kras(G12D) in the pancreas of transgenic mice, using an elastase (EL) promoter, resulted in fibrosis. To identify how Snail modulates inflammation in the pancreas, we examined the effect of expressing Snail in EL-Kras(G12D) mice (Kras(G12D)/Snail) on mast cell infiltration, which has been linked to PDAC progression. Using this animal model system, it was demonstrated that there are increased numbers of mast cells in the pancreas of Kras(G12D)/Snail mice compared with control Kras(G12D) mice. In addition, it was revealed that human primary PDAC tumors with increased Snail expression are associated with increased mast cell infiltration, and that Snail expression in these clinical specimens positively correlated with the expression of stem cell factor (SCF/KITLG), a cytokine known to regulate mast cell migration. Concomitantly, SCF levels are increased in the Kras(G12D)/Snail mice than in control mice. Moreover, overexpression of Snail in PDAC cells increased SCF levels, and the media conditioned by Snail-expressing PDAC cells promoted mast cell migration. Finally, inhibition of SCF using a neutralizing antibody significantly attenuated Snail-induced migration of mast cells. Together, these results elucidate how the EMT regulator Snail contributes to inflammation associated with PDAC tumors.