STAT3 Plays a Critical Role in KRAS -Induced Pancreatic Tumorigenesis
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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 more than 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 premalignant 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 show 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. Cancer Res; 71(14); 5020–9. ©2011 AACR.
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KRAS mutations activate YAP-TAZ and JAK-STAT pathways, leading to release of immunosuppressive cytokines such as CSF-1, IL-4, IL-6.
“KRAS mutations activate Yes-associated protein-tafazzin (YAP-TAZ) and Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways, leading to release of immunosuppressive cytokines such as CSF-1, IL-4, IL-6.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [66]
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“Previous studies have shown that IL-6 is required to promote pancreatic intraepithelial neoplasia progression and PDA development through the activation of STAT3 (Corcoran et al, 2011; Lesina et al, 2011; Zhang et al, 2013).”
BackgroundInflammation as a driver and vulnerability of KRAS mediated oncogenesis
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- Authors
- Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., Levy, D. E., Settleman, J., Engelman, J. A., & Bardeesy, N.
- Affiliations
- Harvard University (US)
- Corresponding author
- Bardeesy, Nabeel
- ORCID
- Venue
- Cancer Research
- Published
- 2011-07-14
- Volume
- 71
- Issue
- 14
- Pages
- 5020-5029
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3693754
- OpenAlex
- W2133591242
- Cited by
- 413
- References
- 51
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 18 · 2023: 32 · 2022: 28 · 2021: 39 · 2020: 30 · 2019: 32 · 2018: 24 · 2017: 35 · 2016: 35 · 2015: 30 · 2014: 32 · 2013: 28 · 2012: 18
- FWCI
- 12.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Fondazione Umberto Veronesi
- National Institutes of Health
- National Cancer Institute (P50CA127003, R01CA133557, P01CA117969, T32CA071345)
- National Institute of Allergy and Infectious Diseases (R0AI28900)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- STAT3, pancreatic ductal adenocarcinoma, JAK2 inhibitors, acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia, premalignant pancreatic lesions, predictive biomarkers
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Humans, Mice, Transgenic, Pancreatic Neoplasms, Phosphorylation, Precancerous Conditions, Genes, ras, Transcriptional Activation, Mice, SCID, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, STAT3 Transcription Factor, Mice
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