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MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-? signaling.

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), which is required for growth and invasion in the collagen-rich microenvironment. In this article, we show that compared with control mice (Kras(+)/MT1-MMP(-)) that express an activating Kras(G12D) mutation necessary for pancreatic cancer development, littermate mice that express both MT1-MMP and Kras(G12D) (Kras(+)/MT1-MMP(+)) developed a greater number of large, dysplastic mucin-containing papillary lesions. These lesions were associated with a significant amount of surrounding fibrosis, increased ?-smooth muscle actin (+) cells in the stroma, indicative of activated myofibroblasts, and increased Smad2 phosphorylation. To further understand how MT1-MMP promotes fibrosis, we established an in vitro model to examine the effect of expressing MT1-MMP in pancreatic ductal adenocarcinoma (PDAC) cells on stellate cell collagen deposition. Conditioned media from MT1-MMP-expressing PDAC cells grown in three-dimensional collagen enhanced Smad2 nuclear translocation, promoted Smad2 phosphorylation, and increased collagen production by stellate cells. Inhibiting the activity or expression of the TGF-? type I receptor in stellate cells attenuated MT1-MMP conditioned medium-induced collagen expression by stellate cells. In addition, a function-blocking anti-TGF-? antibody also inhibited MT1-MMP conditioned medium-induced collagen expression in stellate cells. Overall, we show that the bona fide collagenase MT1-MMP paradoxically contributes to fibrosis by increasing TGF-? signaling and that targeting MT1-MMP may thus help to mitigate fibrosis.

SUBMITTER: Krantz SB

PROVIDER: S-EPMC3196812 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-β signaling.

Krantz Seth B SB Shields Mario A MA Dangi-Garimella Surabhi S Cheon Eric C EC Barron Morgan R MR Hwang Rosa F RF Rao M Sambasiva MS Grippo Paul J PJ Bentrem David J DJ Munshi Hidayatullah G HG

Molecular cancer research : MCR 20110819 10

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), which is required for growth and invasion in the collagen-rich microenvironment. In this article, we show that compared with control mice (Kras(+)/MT1-MMP(-)) that express an act ...[more]

PMID: 21856775

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Project description:Patients with pancreatic cancer, which is characterized by an extensive collagen-rich fibrotic reaction, often present with metastases. A critical step in cancer metastasis is epithelial-to-mesenchymal transition (EMT), which can be orchestrated by the Snail family of transcription factors. To understand the role of Snail (SNAI1) in pancreatic cancer development, we generated transgenic mice expressing Snail in the pancreas. Because chronic pancreatitis can contribute to pancreatic cancer development, Snail-expressing mice were treated with cerulein to induce pancreatitis. Although significant tissue injury was observed, a minimal difference in pancreatitis was seen between control and Snail-expressing mice. However, because Kras mutation is necessary for tumor development in mouse models of pancreatic cancer, we generated mice expressing both mutant Kras(G12D) and Snail (Kras(+)/Snail(+)). Compared with control mice (Kras(+)/Snai(-)), Kras(+)/Snail(+) mice developed acinar ectasia and more advanced acinar-to-ductal metaplasia. The Kras(+)/Snail(+) mice exhibited increased fibrosis, increased phosphorylated Smad2, increased TGF-?2 expression, and activation of pancreatic stellate cells. To further understand the mechanism by which Snail promoted fibrosis, we established an in vitro model to examine the effect of Snail expression in pancreatic cancer cells on stellate cell collagen production. Snail expression in pancreatic cancer cells increased TGF-?2 levels, and conditioned media from Snail-expressing pancreatic cancer cells increased collagen production by stellate cells. Additionally, inhibiting TGF-? signaling in stellate cells attenuated the conditioned media-induced collagen production by stellate cells. Together, these results suggest that Snail contributes to pancreatic tumor development by promoting fibrotic reaction through increased TGF-? signaling.Expression of the EMT regulator Snail in the context of mutant Kras provides new insight into pancreatic cancer progression.

Project description:ObjectivesThere is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.MethodsThe exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.ResultsA total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).ConclusionsThe KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.

Dataset Information

MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-? signaling.

Publications

MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-β signaling.

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