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Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor- signaling in cooperation with active Kras expression

¹ Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA; ² Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA; ³ Vanderbilt University Program in Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA; ⁴ The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor- (TGF-) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-, is deleted or mutated in 55% and the type II TGF- receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras^G12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras^G12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras^G12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras^G12D expression also developed PDAC, which indicated a haploinsufficiency of TGF- signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras^G12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF- signaling and activated Ras signaling cooperate to promote PDAC progression.

[Keywords: Kras; pancreas-specific knockout; pancreatic ductal adenocarcinoma; Ptf1a; TGF-; type II TGF- receptor]

Received July 28, 2006; revised version accepted September 27, 2006.

Juntendo University, Tokyo 113-8421, Japan;

⁶ Osaka University, Osaka 565-0871, Japan.

⁷ Corresponding author.

E-MAIL hal.moses{at}vanderbilt.edu; FAX (615) 936-1790.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/NA

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