Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States and carries a dismal 5-year survival rate of <5% (1
). Activating mutations in the KRAS oncogene are the defining lesion in this malignancy, present in 70–95% of cases (2
). PDAC is believed to arise from precursor lesions called pancreatic intraepithelial neoplasia (PanIN). Molecular pathology analysis of human specimens and the development of genetically engineered mouse models support a model in which PanINs proceed through multiple stages of increasingly severe cellular atypia culminating in the development of invasive carcinoma. This histologic progression is associated with KRAS activation as an early event and the subsequent step-wise accumulation of inactivating mutations in the tumor suppressors, Ink4a/Arf
, and SMAD4
). As this genetic information has not yet led to the development of effective targeted therapeutic strategies in PDAC, there is considerable focus on defining additional molecular pathways driving the progression and maintenance of this disease.
The Signal transducer and activator of transcription (STAT) family transcription factors are constitutively activated in a wide range of human malignancies (7
). STAT proteins are present in the cytoplasm under basal conditions and are activated by phosphorylation on a single tyrosine residue, which triggers dimerization and nuclear localization (8
). Classically, STAT tyrosine phosphorylation is mediated by the Janus (JAK) family of tyrosine kinases, which themselves are activated by cytokine and growth factor receptors (10
). Other tyrosine kinases, such as src, have also been reported to mediate tyrosine phosphorylation of STAT proteins (12
). The STAT proteins were originally identified as factors required for downstream signaling in response to interferon and other inflammatory cytokines (8
). Subsequent studies identified key functions for STAT proteins in the maintenance of self-renewal of embryonic stem cells and in the activation of proliferative, anti-apoptotic and inflammatory pathways to initiate and maintain growth of a number of tumor types (7
STAT3 has been identified as a key oncogenic factor in a number of epithelial malignancies and is required for oncogenesis in mouse models of skin and gastric cancers (15
). In PDAC, constitutive activation of STAT3 by phosphorylation of Tyr705 has been reported in 30–100% of human tumor specimens, as well as in many PDAC cell lines (17
). By contrast, this pathway is inactive in normal pancreas, and correspondingly STAT3 is not required for pancreatic development or homeostasis, as demonstrated by conditional knockout studies in mice (19
). Several lines of evidence suggest that aberrant activation of STAT3 in PDAC is functionally important. Firstly, STAT3 is required for the process of acinar-to-ductal metaplasia (ADM)—thought to be an early event in PDAC pathogenesis—upon ectopic expression of the Pdx1 transcription factor, a key regulator of early pancreatic development (20
). In addition to this potential role in early PDAC, STAT3 has been suggested as a therapeutic target in established PDAC since examination of a limited number of cell lines for the impact of chemical STAT3 pathway inhibitors and dominant-negative STAT3 constructs has shown that the pathway may contribute to the proliferation of some PDAC cell lines in vitro and the tumorigenicity of some PDAC xenografts (17
). These data support the need for more detailed studies to define the basis for STAT3 activation in PDAC and to rigorously establish specific roles for STAT3 in the initiation and progression of PDAC in vivo.
In this study, we examined the sensitivity of a large series of PDAC cells lines to pharmacologic STAT3 inhibition and defined biomarkers of sensitivity as well as key upstream activators of the pathway in this cancer. We also employed genetically engineered mouse models to determine the impact of genetic inactivation of STAT3 on the progression of PDAC. Collectively our results demonstrate that upregulation of the gp130 receptor and strong STAT3 phosphorylation point to a subset of PDAC that are highly sensitive to pharmacologic inhibition of the JAK2/STAT3 pathway, and that STAT3 plays an important role in driving PDAC progression at multiple stages of pancreatic tumorigenesis in vivo, thereby supporting STAT3 as a potential therapeutic target in PDAC.