Abstract 4812: Collagen regulation of Snail expression in pancreatic cancer involves TGF-β1 signaling

Abstract

Abstract Pancreatic cancer, the fourth leading cause of cancer death in the U.S., is associated with pronounced desmoplastic reaction; however, the role of this collagen-rich fibrotic reaction in pancreatic cancer progression is poorly understood. Previously, we had shown that the collagen increased expression of the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP). Now we show that collagen can also increase expression of the zinc-finger transcription factor Snail to enhance pancreatic cancer invasion. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3D collagen gels induced Snail. As we had previously published that TGF-β1 increases Snail levels, we examined the contribution of TGF-β1 signaling to collagen-induced Snail expression. Inhibiting TGF-β1 signaling with siRNA against TGF-β1 receptor type I (TbRI) or with a highly specific inhibitor of TbRI kinase activity attenuated the effect of collagen on Snail levels. To further examine the role of Snail in PDAC progression, we generated Snail-inducible PDAC cells lines. Expression of Snail in PDAC cells grown in 3D collagen gels enhanced invasion, which was blocked in the presence of the MMP inhibitor GM6001. Overexpression of Snail in PDAC cells increased MT1-MMP, while siRNA against Snail decreased MT1-MMP and also attenuated collagen-induced MT1-MMP expression. Snail expression of MT1-MMP requires ERK1/2 signaling and blocking ERK1/2 phosphorylation inhibited Snail-induced invasion in 3D collagen gels. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that collagen-rich milieu can increase the expression of Snail, and suggests that the desmoplastic reaction actively contributes to PDAC progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4812.