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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 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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“Disruption of Stat3 in the developing exocrine pancreas significantly reduced PanIN development, especially those of high-grade, and consequently, these mice had a lower incidence of PDAC tumors (Corcoran et al., 2011; Fukuda et al., 2011; Lesina et al., 2011).”
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Tzatsos, A., Paskaleva, P., Ferrari, F., Deshpande, V., Stoykova, S., Contino, G., Wong, K., Lan, F., Trojer, P., Park, P. J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64535 · Cited by 178
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“kRAS is the oncogenic driver of human pancreatic ductal adenocarcinoma and STAT3 is essential for the progression of kRAS-driven pancreatic ductal adenocarcinoma.(37,38,41,42) We demonstrated that tumor cells respond to activated T cells to activate STAT3.”
BackgroundSTAT3: a multifaceted oncoprotein
Guanizo, A. C., Fernando, C. D., Garama, D. J., & Gough, D. J. (2018) · Growth Factors · doi:10.1080/08977194.2018.1473393 · Cited by 179
“Another IL-6-family cytokine, LIF, also activates STAT3 signalling in numerous cancer types, including glioblastoma, nasopharyngeal carcinoma and pancreatic ductal adenocarcinoma (Corcoran et al., 2011; Liu et al., 2013; Pe~nuelas et al., 2009).”
BackgroundWhat We Have Learned About Pancreatic Cancer From Mouse Models
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“Therefore, Notch seems to be of significance in pancreatic carcinogenesis, and cross-talks amongKras,NFkB,Notch, andCOX-2 in cellular signalingmight contribute to themolecular pathogenesis of pancreatic cancer.”
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Parikh, K., Banna, G., Liu, S. V., Friedlaender, A., Desai, A., Subbiah, V., & Addeo, A. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01375-4 · Cited by 164
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Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?
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“The STAT3 transcription factor is an important regulator of pancreatic tumorigenesis, and for promoting tumor stem cell proliferation and maintaining an inflammatory tumor microenvironment [47].”
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“Abbreviations: aPSCs activated pancreatic stellate cells, qPSCs quiescent pancreatic stellate cells, GFs growth factors, PNI perineural invasion, EMT EpithelialMesenchymal Transition, TME tumor microenvironment, GFAP glial fibrillary acidic protein, α-SMA α-smooth muscle actin, NGF nerve growth factor, FAP-α fibroblas…”
BackgroundInfluentialIntracellular HMGB1 as a novel tumor suppressor of pancreatic cancer
Kang, R., Xie, Y., Zhang, Q., Hou, W., Jiang, Q., Zhu, S., Liu, J., Zeng, D., Wang, H., Bartlett, D. L., et al. (2017) · Cell Research · doi:10.1038/cr.2017.51 · Cited by 137
GEMMs as preclinical models for testing pancreatic cancer therapies
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“Conversely, aberrant Stat3 activation in the pancreas accelerates tumour development Corcoran et al., 2011 Sma/mothers against decapentaplegic family member 4 (SMAD4/ DPC4) Smad4 is a tumour suppressor belonging to the Smad family.”
Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas
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“…have confirmed the ability of pancreatic injury to accelerate PanIN1 to PDAC progression and invoked inflammation-related mechanisms, including COX2 and interleukin-6 induction and STAT3 activation (Corcoran et al., 2011; Guerra et al., 2011; Lesina et al., 2014; Muller-Decker et al., 2006).”
Baer, R., Cintas, C., Dufresne, M., Cassant-Sourdy, S., Schönhuber, N., Planque, L., Lulka, H., Couderc, B., Bousquet, C., Garmy-Susini, B., et al. (2014) · Genes & Development · doi:10.1101/gad.249409.114 · Cited by 129
“It contributes to oncogenic Kras hyperactivation in preneoplastic stages and to the maintenance of essential signaling nodes, including STAT3, NF-kB, and ERK, known to be critical for progression toward cancer lesions (Corcoran et al. 2011; Fukuda et al. 2011; Lesina et al. 2011); similarly, in cancer cells, PI3K was…”
BackgroundInfluentialMetformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer
Chen, K., Qian, W., Jiang, Z., Cheng, L., Li, J., Sun, L., Zhou, C., Gao, L., Lei, M., Yan, B., et al. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0701-0 · Cited by 125
“A previous study has suggested a crucial role for STAT3 signaling in Kras-induced pancreatic tumorigenesis [8].”
BackgroundInfluentialBaumgart, S., Chen, N., Siveke, J. T., König, A. O., Zhang, J., Singh, S. K., Wolf, E., Bartkuhn, M., Esposito, I., Heßmann, E., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0593 · Cited by 122
“Aberrant expression and activation of STAT3 is frequently observed in human pancreatic carcinoma and can favor the progression of PanIN lesions in the transgenic KrasG12D model (36).”
BackgroundIL-17-Producing Cells in Tumor Immunity: Friends or Foes?
Kuen, D., Kim, B., & Chung, Y. (2020) · Immune Network · doi:10.4110/in.2020.20.e6 · Cited by 125
“Regardless of the mechanism by which IL-17 promotes tumor growth, the protumoral properties of IL-17 via STAT3 signaling in cancer cells impact the early stages of oncogenesis rather than the later stages in an established tumor (27,128,129).”
BackgroundMills, L. D., Zhang, Y., Marler, R. J., Herreros‐Villanueva, M., Zhang, L., Almada, L. L., Couch, F. J., Wetmore, C., di Magliano, M. P., & Fernández-Zapico, M. E. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.438846 · Cited by 120
“Recent reports established an activated STAT3 (p-STAT3) in pancreatic cancer biology to be essential for PanIN lesion progression (16, 17, 32).”
BackgroundSox9 and programming of liver and pancreatic progenitors
Kawaguchi, Y. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66022 · Cited by 122
CircRNA_100782 regulates pancreatic carcinoma proliferation through the IL6-STAT3 pathway
Chen, G., Shi, Y., Zhang, Y., & Sun, J. (2017) · OncoTargets and Therapy · doi:10.2147/ott.s150678 · Cited by 122
“Previous studies have revealed that the IL6-JAK2-STAT3 signaling pathway is crucial for cell growth and survival.(21,22) This pathway was frequently activated in pancreatic cell lines and PDAC tissue specimens.”
BackgroundEmerging roles for the IL-6 family of cytokines in pancreatic cancer
van Duijneveldt, G., Griffin, M. D. W., & Putoczki, T. L. (2020) · Clinical Science · doi:10.1042/cs20191211 · Cited by 126
Guo, K., Ma, Q., Li, J., Wang, Z., Shan, T., Li, W., Xu, Q., & Xie, K. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0809 · Cited by 117
“It has been shown to participate in numerous processes key to malignant progression (24, 25).”
BackgroundNagathihalli, N. S., Castellanos, J. A., VanSaun, M. N., Dai, X., Ambrose, M., Guo, Q., Xiong, Y., & Merchant, N. B. (2016) · Oncotarget · doi:10.18632/oncotarget.11786 · Cited by 117
LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker
Bressy, C., Lac, S., Nigri, J., Leca, J., Roques, J., Lavaut, M., Secq, V., Guillaumond, F., Bui, T.-T., Pietrasz, D., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-15-2790 · Cited by 121
IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma
Long, K. B., Tooker, G. M., Tooker, E., Luque, S. L., Lee, J. W., Pan, X., & Beatty, G. L. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0899 · Cited by 112
“For PDAC development, activation of the STAT3 pathway in inflammatory cells is necessary to promote pancreatic intraepithelial neoplasia (PanIN) progression (15, 16).”
BackgroundImportance of STAT3 signalling in cancer, metastasis and therapeutic interventions
El‐Tanani, M., Khatib, A. O. A., Aladwan, S., Abuelhana, A., McCarron, P. A., & Tambuwala, M. M. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110275 · Cited by 115
Goumas, F. A., Holmer, R., Egberts, J. D., Gontarewicz, A., Heneweer, C., Geisen, U. M., Hauser, C., Mende, M., Legler, K., Röcken, C., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29445 · Cited by 115
“They also found a significantly higher expression of gp130 and IL-6 in microarrays of human PDACs compared to matched normal pancreata.(16) A more recent publication highlights IL-6 as a potential therapeutic target, as it is a key player in the maintenance of PanINs and the progression to cancer.”
ResultNever let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer
Giovannetti, E., van der Borden, C. L., Frampton, A. E., Ali, A., Firuzi, O., & Peters, G. J. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.04.006 · Cited by 114
Interleukin-6: a villain in the drama of pancreatic cancer development and progression
Holmer, R., Goumas, F. A., Waetzig, G. H., Rose‐John, S., & Kalthoff, H. (2014) · Hepatobiliary & pancreatic diseases international · doi:10.1016/s1499-3872(14)60259-9 · Cited by 112
Poh, A. R., & Ernst, M. (2021) · Cancers · doi:10.3390/cancers13122860 · Cited by 106
“Classically-activated M1 macrophages initiate ADM via the secretion of inflammatory mediators, including IL6 [61], TNFα, and RANTES [37,62].”
BackgroundInfluentialYang, H., Pinello, C. E., Luo, J., Li, D., Wang, Y., Zhao, L., Jahn, S. C., Saldanha, S. A., Planck, J. L., Geary, K. R., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0930 · Cited by 109
“(31), was exposed to varying doses of L002 or L004.”
BackgroundDenley, S. M., Jamieson, N. B., McCall, P., Oien, K. A., Morton, J. P., Carter, C. R., Edwards, J., & McKay, C. J. (2013) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-013-2168-7 · Cited by 105
Huang, X., Dai, S., Dai, J., Xiao, Y., Bai, Y., Chen, B., & Zhou, M. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s91511 · Cited by 104
Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy
Liu, L., Huang, X., Shi, F., Song, J., Guo, C., Yang, J., Liang, T., & Bai, X. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02273-w · Cited by 105
“The IL-6/STAT3 axis can promote the expansion of immunosuppressive cells and alter the balance of T cell subsets [68, 69].”
BackgroundBlockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer
Wang, M., Fer, N. D., Galeas, J., Collisson, E. A., Kim, S. E., Sharib, J. M., & McCormick, F. P. (2019) · Nature Communications · doi:10.1038/s41467-019-11044-9 · Cited by 101
The Role of Inflammation in Pancreatic Cancer
Hausmann, S., Kong, B., Michalski, C. W., Erkan, M., & Frieß, H. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-3-0348-0837-8_6 · Cited by 101
IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer
He, W., Wu, J., Shi, J., Huo, Y., Dai, W., Geng, J., Lu, P., Yang, M., Fang, Y., Wang, W., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3131 · Cited by 105
Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42
Razidlo, G. L., Burton, K. M., & McNiven, M. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003276 · Cited by 99
“Interestingly, IL-6 – mediated signaling is required for the early progression of pancreatic cancer (5, 6, 8).”
BackgroundRisk factors for pancreatic cancer: underlying mechanisms and potential targets
Kolodecik, T. R., Shugrue, C., Ashat, M., & Thrower, E. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2013.00415 · Cited by 95
“Stat3 has also been shown to be required for the activation and progression of PDAC (Scholz et al., 2003; Corcoran et al., 2011; Fukuda et al., 2011; Lesina et al., 2011).”
BackgroundPotent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer
Smigiel, J. M., Parameswaran, N., & Jackson, M. W. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0337 · Cited by 94
“Furthermore, constitutive activation of oncogenic STAT3 signaling promotes tumorigenesis and is associated with poor outcomes in PDAC (21, 22).”
BackgroundAgarwal, S., Lakoma, A., Chen, Z., Hicks, J. M., Metelitsa, L. S., Kim, E. S., & Shohet, J. M. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2946 · Cited by 93
“Increasing evidence suggests that STAT3-mediated inflammatory processes are critical for tumorigenesis (38-40).”
Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy
Wu, X., Cao, Y., Xiao, H., Li, C., & Lin, J. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0921 · Cited by 96
He, P., Yang, J. W., Yang, V. W., & Bialkowska, A. B. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.12.005 · Cited by 93
JAK/STAT pathway dysregulation in tumors: A Drosophila perspective
Amoyel, M., Anderson, A. M., & Bach, E. A. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.03.023 · Cited by 94
“One emerging theme is that tumorigenesis involves co-operation between oncogenes, such Ras and STAT, in mammals and in flies (Wu et al., 2010; Corcoran et al., 2011; Herranz et al., 2012).”
BackgroundSun, L., Zhang, X., Song, Q., Liu, L., Forbes, M. E., Tian, W., Zhang, Z., Kang, Y., Wang, H., Fleming, J. B., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.12.008 · Cited by 95
“Persistent activation of STAT3 has been demonstrated to be a crucial mediator in governing pancreatic carcinogenesis, acinar-ductal-metaplasia (ADM) development, tumor progression, and inhibition of apoptosis and inflammatory response [32-38].”
BackgroundSynthetic Lethal Vulnerabilities in KRAS-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90
“Numerous other studies have also demonstrated an important role for JAK-STAT signaling in PDAC tumorigenesis (Corcoran et al. 2011; Fukuda et al. 2011; Lesina et al. 2011).”
BackgroundRädler, P. D., Wehde, B. L., & Wagner, K. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.04.025 · Cited by 92
“JAK1 was thought to have a subordinate role for STAT activation, in particular STAT3, during mammary gland development and in breast cancer (Corcoran et al., 2011; Marotta et al., 2011; Abubaker et al., 2014).”
BackgroundRegulation of Cellular Identity in Cancer
Roy, N., & Hebrok, M. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.12.001 · Cited by 97
“In addition, several other pathways in the Ras interactome, such as STAT3 and EGFR signaling, have been shown to play an integral part in the ADM process (Corcoran et al., 2011; Fukuda et al., 2011; Lesina et al., 2011;Siveke et al., 2007;Ardito et al., 2012).”
BackgroundMARSTRAND-DAUCE, L., Lorenzo, D., Chassac, A., Nicole, P., Couvelard, A., & Haumaître, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129946 · Cited by 105
“They include IL6 secretion combined with downstream STAT3 activation [86,87].”
BackgroundCellular determinants and therapeutic implications of inflammation in pancreatic cancer
Stone, M. L., & Beatty, G. L. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.012 · Cited by 87
Komar, H. M., Serpa, G., Kerscher, C., Schwoegl, E., Mace, T. A., Jin, M. L., Yang, M.-C., Chen, C., Bloomston, M., Ostrowski, M. C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01973-0 · Cited by 85
Targeting TGFβR2‐mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer
Huang, H., Zhang, Y., Gallegos, V., Sorrelle, N., Zaid, M. M., Toombs, J., Du, W., Wright, S., Hagopian, M., Wang, Z., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201910515 · Cited by 87
“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
Kitajima, S., Thummalapalli, R., & Barbie, D. A. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.06.009 · Cited by 83
Metadata
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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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