Abstract 515: Membrane type 1-matrix metalloproteinase cooperates with KrasG12D to promote pancreatic fibrosis through transforming growth factor-β activation of pancreatic stellate cells

Abstract

Abstract Pancreatic cancer is associated with a pronounced fibrotic reaction that was recently shown to limit delivery of chemotherapy. To identify potential therapeutic targets to overcome this fibrosis, we examined the interplay between fibrosis and the key proteinase membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) that is required for growth and invasion in the collagen-rich microenvironment. In this report we show that compared to control mice (Kras+/MT1-MMP-) that express an activating mutation necessary for pancreatic cancer development, KrasG12D, littermate mice that express both MT1-MMP and KrasG12D (Kras+/MT1-MMP+) developed a greater number of large mucin-containing papillary lesions with a high degree of cellular atypia. These lesions were associated with a significant amount of surrounding fibrosis, increased α-smooth muscle actin positive cells in the stroma, indicative of activated myofibroblasts, and a greater extent of Smad2 phosphorylation. To further understand how MT1-MMP promotes fibrosis, we established an in vitro co-culture model to examine the effect of expressing MT1-MMP in PDAC cells on stellate cell collagen deposition. Conditioned media from MT1-MMP-expressing PDAC cells grown in 3D collagen enhance Smad2 nuclear translocation, promote Smad2 phosphorylation and increase collagen production by stellate cells. Inhibiting the activity or expression of the TGF-β type I receptor in stellate cells attenuated MT1-MMP-conditioned media induced collagen expression by stellate cells. Additionally, a function-blocking anti-TGF-β antibody also inhibited MT1-MMP-induced collagen mRNA expression in stellate cells. Overall, we demonstrate that the bona fide collagenase MT1-MMP paradoxically contributes to fibrosis in vivo by increasing TGF-β signaling and that targeting MT1-MMP may help to mitigate fibrosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 515. doi:10.1158/1538-7445.AM2011-515