Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer
Open accessAbstract
Physiological levels of Kras(G12D) are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras(G12D), IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development.
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IL-6 signaling facilitates the progression of pre-neoplastic lesions to malignant forms, and negative feedback by SOCS3 proteins decreases primary tumor growth.
“IL-6 signaling facilitates the progression of pre-neoplastic lesions to malignant forms, and negative feedback by SOCS3 proteins was found to decrease primary tumor growth.”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [45]
The Discussion (page unavailable) states that IL-6 transsignaling promotes progression of preneoplastic pancreatic lesions and development of pancreatic cancer. The Results (page unavailable) identify SOCS3 as a negative-feedback inhibitor and show that deleting it accelerates lesion progression and shortens tumor latency. The paper does not establish that SOCS3 feedback decreases the growth of an existing primary tumor. (LLM, conf=0.86)
Experimental — accuracy not yet measuredK-RAS-induced activation of NF-κB is required for pancreatic cancer development, which depends on IL-6 trans-signaling-mediated STAT3 activation.
“Mutated K-RAS activates NF-κB in a mouse model of lung cancer (315), and the K-RAS-induced activation of NF-κB is required for pancreatic cancer development (316), which depends on IL-6 trans-signaling-mediated STAT3 activation (317).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [317]
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Hidalgo, M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0901557 · Cited by 2,570 · see citing works
Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · cited 1× · see citing works
“(Trp53, Ink4A/Arf) in genetically engineered mice (GEM) recapitulates PanIN initiation and progression to pancreatic cancer (PC), similar to the clinical pathology (Aguirre et al., 2003; Guerra et al., 2007; Hingorani et al., 2003, 2005; Kelly et al., 2008).”
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Research works printed but not linked: 44
- [2]2. Algul, H. ∙ Treiber, M. ∙ Lesina, M. ... Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis J. Clin. Invest. 2007; 117:1490-1501 Crossref Scopus (158) PubMed Google Scholar
- [3]3. Algul, H. ∙ Treiber, M. ∙ Lesina, M. ... Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells? Nat. Clin. Pract. Gastroenterol. Hepatol. 2007; 4:454-462 Crossref Scopus (92) PubMed Google Scholar
- [4]4. Algul, H. ∙ Wagner, M. ∙ Lesina, M. ... Overexpression of ErbB2 in the exocrine pancreas induces an inflammatory response but not increased proliferation Int. J. Cancer. 2007; 121:1410-1416 Crossref Scopus (14) PubMed Google Scholar
- [5]5. Barre, B. ∙ Vigneron, A. ∙ Coqueret, O. The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25A promoter J. Biol. Chem. 2005; 280:15673-15681 Full Text Full Text (PDF) Scopus (79) PubMed Google Scholar
- [6]6. Bollrath, J. ∙ Phesse, T.J. ∙ von Burstin, V.A. ... gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis Cancer Cell. 2009; 15:91-102 Full Text Full Text (PDF) Scopus (820) PubMed Google Scholar
- [7]7. Chalaris, A. ∙ Rabe, B. ∙ Paliga, K. ... Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils Blood. 2007; 110:1748-1755 Crossref Scopus (280) PubMed Google Scholar
- [8]8. Clark, C.E. ∙ Hingorani, S.R. ∙ Mick, R. ... Dynamics of the immune reaction to pancreatic cancer from inception to invasion Cancer Res. 2007; 67:9518-9527 Crossref Scopus (793) PubMed Google Scholar
- [9]9. Ebrahimi, B. ∙ Tucker, S.L. ∙ Li, D. ... Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis Cancer. 2004; 101:2727-2736 Crossref Scopus (273) PubMed Google Scholar
- [10]10. Finco, T.S. ∙ Westwick, J.K. ∙ Norris, J.L. ... Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation J. Biol. Chem. 1997; 272:24113-24116 Full Text Full Text (PDF) Scopus (337) PubMed Google Scholar
- [12]12. Greten, F.R. ∙ Weber, C.K. ∙ Greten, T.F. ... Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis Gastroenterology. 2002; 123:2052-2063 Full Text Full Text (PDF) Scopus (154) PubMed Google Scholar
- [13]13. Grivennikov, S. ∙ Karin, E. ∙ Terzic, J. ... IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer Cancer Cell. 2009; 15:103-113 Full Text Full Text (PDF) Scopus (1796) PubMed Google Scholar
- [14]14. Guerra, C. ∙ Schuhmacher, A.J. ∙ Canamero, M. ... Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice Cancer Cell. 2007; 11:291-302 Full Text Full Text (PDF) Scopus (965) PubMed Google Scholar
- [15]15. He, G. ∙ Yu, G.Y. ∙ Temkin, V. ... Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation Cancer Cell. 2010; 17:286-297 Full Text Full Text (PDF) Scopus (386) PubMed Google Scholar
- [16]16. Hidalgo, M. Pancreatic cancer N. Engl. J. Med. 2010; 362:1605-1617 Crossref Scopus (2419) PubMed Google Scholar
- [17]17. Hingorani, S.R. ∙ Petricoin, E.F. ∙ Maitra, A. ... Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse Cancer Cell. 2003; 4:437-450 Full Text Full Text (PDF) Scopus (1950) PubMed Google Scholar
- [18]18. Hingorani, S.R. ∙ Wang, L. ∙ Multani, A.S. ... Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice Cancer Cell. 2005; 7:469-483 Full Text Full Text (PDF) Scopus (1934) PubMed Google Scholar
- [19]19. Hruban, R.H. ∙ Adsay, N.V. ∙ Albores-Saavedra, J. ... Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations Cancer Res. 2006; 66:95-106 Crossref Scopus (329) PubMed Google Scholar
- [20]20. Hutzen, B. ∙ Friedman, L. ∙ Sobo, M. ... Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas Int. J. Oncol. 2009; 35:867-872 PubMed Google Scholar
- [21]21. Jackson, E.L. ∙ Willis, N. ∙ Mercer, K. ... Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras Genes Dev. 2001; 15:3243-3248 Crossref Scopus (1540) PubMed Google Scholar
- [22]22. Kawesha, A. ∙ Ghaneh, P. ∙ Andren-Sandberg, A. ... K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16(INK4A), p21(WAF-1), cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma Int. J. Cancer. 2000; 89:469-474 Crossref Scopus (139) PubMed Google Scholar
- [23]23. Kelly, K.A. ∙ Bardeesy, N. ∙ Anbazhagan, R. ... Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma PLoS Med. 2008; 5:e85 Crossref Scopus (196) PubMed Google Scholar
- [24]24. Kim, D. ∙ Sun, M. ∙ He, L. ... A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation J. Biol. Chem. 2010; 285:8383-8394 Full Text Full Text (PDF) Scopus (50) PubMed Google Scholar
- [25]25. Kocher, H.M. ∙ Mears, L. ∙ Lea, N.C. ... JAK V617F missense mutation is absent in pancreatic cancer Gut. 2007; 56:1174-1175 Crossref Scopus (13) PubMed Google Scholar
- [26]26. Kurahara, H. ∙ Shinchi, H. ∙ Mataki, Y. ... Significance of M2-polarized tumor-associated macrophage in pancreatic cancer J. Surg. Res. 2009; in press. Published online June 16, 2009 Crossref PubMed Google Scholar
- [27]27. Lin, J. ∙ Jin, X. ∙ Rothman, K. ... Modulation of signal transducer and activator of transcription 3 activities by p53 tumor suppressor in breast cancer cells Cancer Res. 2002; 62:376-380 PubMed Google Scholar
- [28]28. Lin, L. ∙ Hutzen, B. ∙ Li, P.K. ... A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells Neoplasia. 2010; 12:39-50 Crossref Scopus (185) PubMed Google Scholar
- [29]29. Lin, L. ∙ Hutzen, B. ∙ Zuo, M. ... Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells Cancer Res. 2010; 70:2445-2454 Crossref Scopus (209) PubMed Google Scholar
- [30]30. Lowenfels, A.B. ∙ Maisonneuve, P. ∙ Cavallini, G. ... Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group N. Engl. J. Med. 1993; 328:1433-1437 Crossref Scopus (1590) PubMed Google Scholar
- [31]31. Luttges, J. ∙ Neumann, S. ∙ Jesnowski, R. ... Lack of apoptosis in PanIN-1 and PanIN-2 lesions associated with pancreatic ductal adenocarcinoma is not dependent on K-ras status Pancreas. 2003; 27:e57-e62 Crossref Scopus (16) PubMed Google Scholar
- [32]32. Marrache, F. ∙ Tu, S.P. ∙ Bhagat, G. ... Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis Gastroenterology. 2008; 135:1277-1287 Full Text Full Text (PDF) Scopus (85) PubMed Google Scholar
- [33]33. Masuda, M. ∙ Suzui, M. ∙ Yasumatu, R. ... Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma Cancer Res. 2002; 62:3351-3355 PubMed Google Scholar
- [34]34. Matthews, V. ∙ Schuster, B. ∙ Schutze, S. ... Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE) J. Biol. Chem. 2003; 278:38829-38839 Full Text Full Text (PDF) Scopus (335) PubMed Google Scholar
- [35]35. Nakaya, M. ∙ Hashimoto, M. ∙ Nakagawa, R. ... SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis J. Immunol. 2009; 183:7047-7053 Crossref Scopus (40) PubMed Google Scholar
- [36]36. Nakhai, H. ∙ Sel, S. ∙ Favor, J. ... Ptf1a is essential for the differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in the mouse retina Development. 2007; 134:1151-1160 Crossref Scopus (161) PubMed Google Scholar
- [37]37. Rabe, B. ∙ Chalaris, A. ∙ May, U. ... Transgenic blockade of interleukin 6 transsignaling abrogates inflammation Blood. 2008; 111:1021-1028 Crossref Scopus (217) PubMed Google Scholar
- [38]38. Reid, T. ∙ Jin, X. ∙ Song, H. ... Modulation of Janus kinase 2 by p53 in ovarian cancer cells Biochem. Biophys. Res. Commun. 2004; 321:441-447 Crossref Scopus (11) PubMed Google Scholar
- [39]39. Rose-John, S. ∙ Heinrich, P.C. Soluble receptors for cytokines and growth factors: generation and biological function Biochem. J. 1994; 300:281-290 Crossref Scopus (712) PubMed Google Scholar
- [40]40. Rose-John, S. ∙ Scheller, J. ∙ Elson, G. ... Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer J. Leukoc. Biol. 2006; 80:227-236 Crossref Scopus (547) PubMed Google Scholar
- [41]41. Sano, S. ∙ Itami, S. ∙ Takeda, K. ... Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis EMBO J. 1999; 18:4657-4668 Crossref Scopus (450) PubMed Google Scholar
- [42]42. Sawai, H. ∙ Funahashi, H. ∙ Matsuo, Y. ... Expression and prognostic roles of integrins and interleukin-1 receptor type I in patients with ductal adenocarcinoma of the pancreas Dig. Dis. Sci. 2003; 48:1241-1250 Crossref Scopus (30) PubMed Google Scholar
- [43]43. Scholz, A. ∙ Heinze, S. ∙ Detjen, K.M. ... Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer Gastroenterology. 2003; 125:891-905 Full Text Full Text (PDF) Scopus (222) PubMed Google Scholar
- [44]44. Sipos, B. ∙ Moser, S. ∙ Kalthoff, H. ... A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform Virchows Arch. 2003; 442:444-452 Crossref Scopus (276) PubMed Google Scholar
- [45]45. Talar-Wojnarowska, R. ∙ Gasiorowska, A. ∙ Smolarz, B. ... Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis Dig. Dis. Sci. 2009; 54:683-689 Crossref Scopus (86) PubMed Google Scholar
- [46]46. Trevino, J.G. ∙ Gray, M.J. ∙ Nawrocki, S.T. ... Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells Angiogenesis. 2006; 9:101-110 Crossref Scopus (42) PubMed Google Scholar
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Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008) · Nature · doi:10.1038/nature07205 · Cited by 11,399 · see citing works
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von Figura, G., Fukuda, A., Roy, N., Liku, M. E., Morris IV, J. P., Kim, G. E., Russ, H. A., Firpo, M. A., Mulvihill, S. J., Dawson, D. W., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb2916 · Cited by 190 · see citing works
Kang, R., Loux, T., Tang, D., Schapiro, N. E., Vernon, P., Livesey, K. M., Krasinskas, A., Lotze, M. T., & Zeh, H. J. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113865109 · Cited by 163 · see citing works
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Yin, Y., Liu, W., & Dai, Y. (2015) · Human Immunology · doi:10.1016/j.humimm.2015.09.037 · Cited by 113 · see citing works
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Chikuma, S., Kanamori, M., Mise‐Omata, S., & Yoshimura, A. (2017) · Cancer Science · doi:10.1111/cas.13194 · Cited by 112 · see citing works
Self-citationFlandez, M., Cendrowski, J., Cañamero, M., Salas, A., del Pozo, N., Schoonjans, K., & Real, F. X. (2014) · Gut · doi:10.1136/gutjnl-2012-304381 · Cited by 95 · see citing works
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Velez-Delgado, A., Donahue, K. L., Brown, K. L., Du, W., Irizarry-Negron, V., Menjivar, R. E., Lasse Opsahl, E. L., Steele, N. G., The, S., Lazarus, J., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.02.016 · Cited by 91 · see citing works
Huang, L., Hu, B., Ni, J., Wu, J., Jiang, W., Chen, C., Yang, L., Zeng, Y., Wan, R., Hu, G., et al. (2016) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-016-0301-7 · Cited by 86 · see citing works
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Cullis, J., Das, S., & Bar-Sagi, D. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031849 · Cited by 85 · see citing works
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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 · see citing works
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BackgroundPerusina Lanfranca, M., Zhang, Y., Girgis, A., Kasselman, S., Lazarus, J., Kryczek, I., Delrosario, L., Rhim, A., Koneva, L., Sartor, M., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.12.010 · Cited by 81 · see citing works
Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression
Rielland, M., Cantor, D. J., Graveline, R., Hajdu, C., Mara, L., de Diego Diaz, B., Miller, G., & David, G. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72619 · Cited by 76 · see citing works
Circumventing senescence is associated with stem cell properties and metformin sensitivity
Deschênes‐Simard, X., Parisotto, M., Rowell, M., Le Calvé, B., Igelmann, S., Moineau‐Vallée, K., Saint‐Germain, E., Kalegari, P., Bourdeau, V., Kottakis, F., et al. (2019) · Aging Cell · doi:10.1111/acel.12889 · Cited by 45 · see citing works
Tsukamoto, H., Fujieda, K., Hirayama, M., Ikeda, T., Yuno, A., Matsumura, K., Fukuma, D., Araki, K., Mizuta, H., Nakayama, H., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2446 · Cited by 53 · see citing works
Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern
Kim, H. W., Lee, J.-C., Paik, K.-H., Kang, J., Kim, J., & Hwang, J.-H. (2017) · Medicine · doi:10.1097/md.0000000000005926 · Cited by 52 · see citing works
Frank, K. J., Mulero-Sánchez, A., Berninger, A., Ruiz-Cañas, L., Bosma, A., Görgülü, K., Wu, N., Diakopoulos, K. N., Kaya-Aksoy, E., Ruess, D. A., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100815 · Cited by 40 · see citing works
Self-citationThe Regenerative Activity of Interleukin-6
Galun, E., & Rose-John, S. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-308-4_4 · Cited by 34 · see citing works
Self-citationAlonso, V., Escudero, P., Fernández-Martos, C., Salud, A., Méndez, M., Gallego, J., Rodriguez, J.-R., Martín-Richard, M., Fernández-Plana, J., Manzano, H., et al. (2018) · Neoplasia · doi:10.1016/j.neo.2018.05.004 · Cited by 10 · see citing works
Blaszczak, W., White, B., Monterisi, S., & Swietach, P. (2024) · Cell Reports · doi:10.1016/j.celrep.2023.113612 · Cited by 9 · see citing works
- Authors
- Lesina, M., Kurkowski, M. U., Ludes, K., Rose-John, S., Treiber, M., Klöppel, G., Yoshimura, A., Reindl, W., Sipos, B., Akira, S., Schmid, R. M., & Algül, H.
- Affiliations
- TUM Klinikum (DE)
- Technical University of Munich (DE)
- Keio University (JP)
- Universitätsklinikum Tübingen (DE)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Schmid, Roland M.
- Algül, Hana
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 19
- Issue
- 4
- Pages
- 456-469
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2152181022
- Cited by
- 862
- References
- 2
- Citations by year
- 2026: 34 · 2025: 28 · 2024: 50 · 2023: 37 · 2022: 52 · 2021: 69 · 2020: 67 · 2019: 54 · 2018: 59 · 2017: 80 · 2016: 84 · 2015: 55 · 2014: 61 · 2013: 60 · 2012: 39
- FWCI
- 29.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 838 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Else Kröner-Fresenius-Stiftung (2010_A144)
- Technische Universität München
- Deutsche Krebshilfe (10994)
- National Institute of Biomedical Innovation
- Deutsche Forschungsgemeinschaft (SFB 576, SFB 877)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- STAT3, SOCS3, pancreatic intraepithelial neoplasia, pancreatic ductal adenocarcinoma, KRAS G12D, oncogenic KRAS
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Animals, Female, Humans, Male, Mice, Inbred C57BL, Middle Aged, Pancreatic Neoplasms, Genes, ras, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins p21(ras), Disease Progression, Carcinoma, Pancreatic Ductal, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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