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

  1. Hideaki Ijichi1,
  2. Anna Chytil1,4,
  3. Agnieszka E. Gorska1,4,
  4. Mary E. Aakre1,4,
  5. Yoshio Fujitani2,3,5,
  6. Shuko Fujitani2,3,6,
  7. Christopher V.E. Wright2,3, and
  8. Harold L. Moses1,4,7
  1. 1 Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
  2. 2 Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
  3. 3 Vanderbilt University Program in Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, USA;
  4. 4 The Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA
  1. 5 Present addresses:

    5 Juntendo University, Tokyo 113-8421, Japan;

  2. 6 Osaka University, Osaka 565-0871, Japan.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-β (TGF-β) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the type II TGF-β 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 (KrasG12D) 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 KrasG12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with KrasG12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with KrasG12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined KrasG12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.

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