STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis

Abstract

The STAT3 transcription factor is an important regulator of stem cell self-renewal, cancer cell survival, and inflammation. In the pancreas, STAT3 is dispensable for normal development whereas the majority of pancreatic ductal adenocarcinomas (PDAC) show constitutive activation of STAT3, suggesting its potential as a therapeutic target in this cancer. Here, we sought to define the mechanisms of STAT3 activation and its functional importance in PDAC pathogenesis. Large-scale screening of cancer cell lines with a JAK2 inhibitor that blocks STAT3 function revealed a >30-fold range in sensitivity in PDAC, and showed a close correlation of sensitivity with levels of tyrosine-phosphorylated STAT3 and of the gp130 receptor, an upstream signaling component. Correspondingly, upregulation of the IL6/LIF-gp130 pathway accounted for the strong STAT3 activation in PDAC subsets. To define functions of STAT3 in vivo, we developed mouse models that test the impact of conditional inactivation of STAT3 in KRAS-driven PDAC. We showed that STAT3 is required for the development of the earliest pre-malignant pancreatic lesions, acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Moreover, acute STAT3 inactivation blocked PDAC initiation in a second in vivo model. Our results demonstrate that STAT3 has critical roles throughout the course of PDAC pathogenesis, supporting the development of therapeutic approaches targeting this pathway. Moreover, our work suggests that gp130 and phospho-STAT3 expression may be effective biomarkers for predicting response to JAK2 inhibitors.

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…4A). Signaling pathways including PI3K/S6, ERK, STAT3, and β-catenin have been reported to be activated in PDAC (3,30,31). As expected, these pathways were prominently up-regulated in the PKC pancreata (Fig.…”

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

“…These are two new and important findings because previous studies have suggested that JAK1 and JAK2 are capable of activating STAT3 in response to inflammatory cytokines in diverse cell culture models (reviewed by Kisseleva et al [20]). Although it was recognized nearly 2 decades ago that JAK1 plays a role in IL-6 signaling (21,45,46), more recent work has singled out JAK2 as the master regulator for STAT3 activation in breast cancer and other malignancies (47)(48)(49). This paradigm is likely the result of the fact that pharmacological agents labeled "JAK2 inhibitors" were being utilized in most of the recently published experiments.…”

Building up the tension between the epithelial and stromal compartment in pancreatic ductal adenocarcinoma

“…Thus, these new findings unveil a novel epithelial − stromal crosstalk with profound implications for tumour composition and progression. In light of this study and previous results that highlighted the role of STAT3 in PDAC development, 11 the identification of any pathways that stimulate STAT3 signalling in PDAC may reveal additional therapeutic opportunities.…”