Tgf beta r1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer

Transforming Growth Factor Beta (TGFβ) signaling plays dual roles in pancreatic tumor development. In vivo loss of either Smad4 or Tgfbr2 promotes pancreatic adenocarcinoma in mice expressing mutant Kras. Conversely, pharmacologically-induced reduction in Tgfbr1 kinase activity attenuates growth and metastasis of Panc1 cells orthotopically injected into mouse pancreas. To dissect the role of TGF-β signaling in pancreatic cancer development, we crossed Elastase-Kras (EL-Kras) mice with Tgfbr1 heterozygous knockout mice to generate EL-Kras/Tgfbr1+/− mice. These EL-Kras/Tgfbr1+/− mice and EL-Kras/Tgfbr1+/+ mice from the same litter, as well as the EL-Kras F1 mice (FVB crossed one generation into C57BL/6), were euthanized at 6-9 months of age to compare the incidence, frequency, and size of precancerous lesions in the pancreas. We observed a 65% decrease in the incidence of precancerous lesionsin EL-Kras/Tgfbr1+/− mice as compared to 100% of EL-Kras F1 mice atsix to eight months of age. The frequency of precancerous lesions was also reduced from 11 pre-cancerous lesions per animal to 3, representing a 3.5-fold decrease. More significantly, the levels of fibrosis around pre-cancerous lesions and normal-appearing were dramatically reduced in EL-Kras/Tgfbr1+/− mice. In addition, EL-Kras/Tgfbr1+/− mice showed reduced lipoatrophy and lymphocytic infiltration, compared to their EL-Kras/Tgfbr1+/+ counterparts. It has been recently shown that Pdx1-Cre/LSL-Kras mice with hetero- or homozygous loss of either Smad4 or Tgfbr2 alleles develop pancreatic adenocarcinoma within 2-4 months of age. Likewise, previous findings in EL-Kras/MT-Tgfbr2-DNR mice in two distinct strains demonstrated a 2-3 fold increase in mutant Kras-induced precancerous lesions in the pancreas. In our system, EL-Kras/Tgfbr1 heterozygous null mice have a significantly reduced propensity of developing carcinoma in situ and accompanying phenotypes. In particular, there is a dramatic reduction in focal and diffuse fibrosis and less lymphocytic infiltration. These findings correlate with TGF-β signals that increase ECM deposition and augment immune responses and strongly suggest that Tgfbr1 haploinsufficiency may have a protective role with respect to pancreatic cancer development.