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- W2077497513 abstract "Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival of ∼5%. A hallmark of PDAC is desmoplastic reaction (DR), the pronounced stromal reaction composed of extracellular matrix proteins along with activated fibroblasts, immune cells and endothelial cells. Although it has been suggested that the DR may be responsible for drug resistance, the mechanism is not well deciphered. We now show that collagen type I, the major component of DR, helps PDAC cells override the cell cycle checkpoint arrest induced by gemcitabine, the most commonly used chemotherapy for PDAC. Relative to cells grown on tissue culture plastic, PDAC cells grown in 3D type I collagen gels demonstrated decreased activating phosphorylation of the checkpoint protein Chk1 following gemcitabine treatment. Interestingly, PDAC cells grown atop 3D collagen gels were more sensitive to gemcitabine treatment and demonstrated higher phospho-Chk1 levels compared to cells growing within 3D collagen gels, suggesting that collagen functions as a barrier to drug delivery. As we had previously shown that collagen could induce expression of the key collagenase membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) by PDAC cells, we examined the contribution of MT1-MMP to drug resistance in our model system. Downregulating MT1-MMP with siRNA attenuated the effect of collagen on gemcitabine-induced checkpoint arrest. In contrast, MT1-MMP overexpression further protected the cells from gemcitabine-induced checkpoint arrest. Overall, our results demonstrate the complex interplay between the proteinase MT1-MMP and its substrate type I collagen in regulating chemotherapy resistance, and suggests that targeting MT1-MMP could help overcome PDAC drug resistance. 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 3933." @default.
- W2077497513 created "2016-06-24" @default.
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- W2077497513 date "2010-04-15" @default.
- W2077497513 modified "2023-09-26" @default.
- W2077497513 title "Abstract 3933: Collagen-proteinase cross-talk promotes gemcitabine resistance in pancreatic cancer" @default.
- W2077497513 doi "https://doi.org/10.1158/1538-7445.am10-3933" @default.
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