Interleukin 22 signaling regulates acinar cell plasticity to promote pancreatic tumor development in mice
Open accessAbstract
Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that invades surrounding structures and metastasizes rapidly. Although inflammation is associated with tumor formation and progression, little is known about the mechanisms of this connection. We investigate the effects of interleukin (IL) 22 in the development of pancreatic tumors in mice. Methods We performed studies with Pdx1-Cre;LSL-Kras G12D ;Trp53 +/– ;Rosa26 EYFP/+ (PKCY) mice, which develop pancreatic tumors, and PKCY mice with disruption of IL22 (PKCY Il22 –/– mice). Pancreata were collected at different stages of tumor development and analyzed by immunohistochemistry, immunoblotting, real-time polymerase chain reaction, and flow cytometry. Some mice were given cerulean to induce pancreatitis. Pancreatic cancer cell lines (PD2560) were orthotopically injected into C57BL/6 mice or Il22 –/– mice, and tumor development was monitored. Pancreatic cells were injected into the tail veins of mice, and lung metastases were quantified. Acini were collected from C57BL/6 mice and resected human pancreata and were cultured. Cell lines and acini cultures were incubated with IL22 and pharmacologic inhibitors, and protein levels were knocked down with small hairpin RNAs. We performed immunohistochemical analyses of 26 PDACs and 5 nonneoplastic pancreas specimens. Results We observed increased expression of IL22 and the IL22 receptor (IL22R) in the pancreas compared with other tissues in mice; IL22 increased with pancreatitis and tumorigenesis. Flow cytometry indicated that the IL22 was produced primarily by T-helper 22 cells. PKCY Il22 –/– mice did not develop precancerous lesions or pancreatic tumors. The addition of IL22 to cultured acinar cells increased their expression of markers of ductal metaplasia; these effects of IL22 were prevented with inhibitors of Janus kinase signaling to signal transducer and activator of transcription (STAT) (ruxolitinib) or mitogen-activated protein kinase kinase (MEK) (trametinib) and with STAT3 knockdown. Pancreatic cells injected into Il22 –/– mice formed smaller tumors than those injected into C57BL/6. Incubation of IL22R-expressing PDAC cells with IL22 promoted spheroid formation and invasive activity, resulting in increased expression of stem-associated transcription factors (GATA4, SOX2, SOX17, and NANOG), and increased markers of the epithelial–mesenchymal transition (CDH1, SNAI2, TWIST1, and beta catenin); ruxolitinib blocked these effects. Human PDAC tissues had higher levels of IL22, phosphorylated STAT3, and markers of the epithelial–mesenchymal transition than nonneoplastic tissues. An increased level of STAT3 in IL22R-positive cells was associated with shorter survival times of patients. Conclusions We found levels of IL22 to be increased during pancreatitis and pancreatic tumor development and to be required for tumor development and progression in mice. IL22 promotes acinar to ductal metaplasia, stem cell features, and increased expression of markers of the epithelial–mesenchymal transition; inhibitors of STAT3 block these effects. Increased expression of IL22 by PDACs is associated with reduced survival times.
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Other T cell populations in the PDAC TME, including Th17, Th22, CD4, and γδ T cells, play protumorigenic roles.
“Other T cell populations within the TME have all been noted to play protumorigenic roles, including Th17, Th22, CD4, and γδ T cells188–191”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [189]
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Cites
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
Self-citationOrganoid models of human and mouse ductal pancreatic cancer
Boj, S. F., Hwang, C.-I., Baker, L. A., Chio, I. I. C., Engle, D. D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M. S., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.021 · Cited by 2,150 · see citing works
EMT and Dissemination Precede Pancreatic Tumor Formation
Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., Reichert, M., Beatty, G. L., Rustgi, A. K., Vonderheide, R. H., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.025 · Cited by 2,136 · see citing works
Self-citationPancreatitis and the Risk of Pancreatic Cancer
Lowenfels, A. B., Maisonneuve, P., Cavallini, G., Ammann, R., Lankisch, P. G., Andersen, J. R., DiMagno, E. P., Andrén‐Sandberg, Å., & Domellöf, L. (1993) · New England Journal of Medicine · doi:10.1056/nejm199305203282001 · Cited by 1,753 · see citing works
Epithelial Mesenchymal Transition in Tumor Metastasis
Mittal, V. (2018) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020117-043854 · Cited by 1,528 · see citing works
Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1134 · Cited by 1,400 · see citing works
Guerra, C., Schuhmacher, A. J., Cañamero, M., Grippo, P. J., Verdaguer, L., Pérez-Gallego, L., Dubus, P., Sandgren, E. P., & Barbacid, M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.012 · Cited by 1,224 · see citing works
Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration
Lindemans, C. A., Calafiore, M., Mertelsmann, A. M., O'Connor, M. H., Dudakov, J. A., Jenq, R. R., Velardi, E., Young, L. F., Smith, O. M., Lawrence, G., et al. (2015) · Nature · doi:10.1038/nature16460 · Cited by 1,112 · see citing works
Sonnenberg, G. F., Fouser, L. A., & Artis, D. (2011) · Nature Immunology · doi:10.1038/ni.2025 · Cited by 1,041 · see citing works
Hereditary Pancreatitis and the Risk of Pancreatic Cancer
Lowenfels, A. B., Maisonneuve, P., DiMagno, E. P., Elitsur, Y., Gates, L. K., Perrault, J., Whitcomb, D. C., & International Hereditary Pancreatitis Study Group (1997) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/89.6.442 · Cited by 988 · see citing works
Lesina, M., Kurkowski, M. U., Ludes, K., Rose-John, S., Treiber, M., Klöppel, G., Yoshimura, A., Reindl, W., Sipos, B., Akira, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.009 · Cited by 862 · see citing works
Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Self-citationHuang, L., Holtzinger, A., Jagan, I., BeGora, M. D., Lohse, I., Ngai, N., Nostro, M. C., Wang, R., Muthuswamy, L. B., Crawford, H. C., et al. (2015) · Nature Medicine · doi:10.1038/nm.3973 · Cited by 745 · see citing works
Self-citationIL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine
Huber, S., Gagliani, N., Zenewicz, L. A., Huber, F. J., Bosurgi, L., Hu, B., Hedl, M., Zhang, W. K., O’Connor, W., Murphy, A. J., et al. (2012) · Nature · doi:10.1038/nature11535 · Cited by 713 · see citing works
Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model
Kirchberger, S., Royston, D. J., Boulard, O., Thornton, E., Franchini, F., Szabady, R. L., Harrison, O., & Powrie, F. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20122308 · Cited by 529 · see citing works
Addressing the challenges of pancreatic cancer: Future directions for improving outcomes
Hidalgo, M. M., Cascinu, S., Kleeff, J. H., Labianca, R., Löhr, M. J., Neoptolemos, J. P., Real, F. X., Laethem, J. V., & Heinemann, V. (2014) · Pancreatology · doi:10.1016/j.pan.2014.10.001 · Cited by 507 · see citing works
McAllister, F., Bailey, J. M., Alsina, J., Nirschl, C. J., Sharma, R., Fan, H., Rattigan, Y., Roeser, J. C., Lankapalli, R. H., Zhang, H., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.014 · Cited by 405 · see citing works
Kryczek, I., Lin, Y., Nagarsheth, N., Peng, D., Zhao, L., Zhao, E., Vatan, L., Szeliga, W., Dou, Y., Owens, S. R., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.03.010 · Cited by 389 · see citing works
Self-citationLong, K. B., Gladney, W. L., Tooker, G. M., Graham, K. L., Fraietta, J. A., & Beatty, G. L. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1032 · Cited by 272 · see citing works
Zhang, Y., Yan, W., Collins, M. A., Bednar, F., Rakshit, S., Zetter, B. R., Stanger, B. Z., Chung, I., Rhim, A. D., & di Magliano, M. P. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1558-t · Cited by 261 · see citing works
Self-citationPark, O., Wang, H., Weng, H., Feigenbaum, L., Li, H., Yin, S., Ki, S. H., Yoo, S. H., Dooley, S., Wang, F., et al. (2011) · Hepatology · doi:10.1002/hep.24339 · Cited by 242 · see citing works
Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer
Whitcomb, D. C. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00115.2004 · Cited by 197 · see citing works
GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer
Waghray, M., Yalamanchili, M., Dziubinski, M. L., Zeinali, M., Erkkinen, M., Yang, H., Schradle, K. A., Urs, S., di Magliano, M. P., Welling, T. H., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0947 · Cited by 197 · see citing works
Inflammatory Mechanisms Contributing to Pancreatic Cancer Development
Farrow, B. J., Sugiyama, Y., Chen, A., Uffort, E., Nealon, W., & Evers, B. (2004) · Annals of Surgery · doi:10.1097/01.sla.0000128681.76786.07 · Cited by 179 · see citing works
Acinar Cells of the Pancreas Are a Target of Interleukin-22
Aggarwal, S., Xie, M.-H., Maruoka, M., Foster, J., & Gurney, A. L. (2001) · Journal of Interferon & Cytokine Research · doi:10.1089/107999001317205178 · Cited by 170 · see citing works
The role of the IL-22/IL-22R1 axis in cancer
Lim, C., & Savan, R. (2014) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2014.04.005 · Cited by 162 · see citing works
Xue, J., Zhao, Q., Sharma, V., Nguyen, L. P., Lee, Y. N., Pham, K. L., Edderkaoui, M., Pandol, S. J., Park, W., & Habtezion, A. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.09.064 · Cited by 146 · see citing works
Biological and pathological activities of interleukin-22
Lanfranca, M. P., Lin, Y., Fang, J., Zou, W., & Frankel, T. L. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1391-6 · Cited by 141 · see citing works
Self-citationPancreatic Cancer and Tumor Microenvironment
Grippo, P. J., & Munshi, H. G. (2012) · Cited by 131 · see citing works
Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas
Cobo, I., Martinelli, P., Flández, M., Bakiri, L., Zhang, M.-F., Pau, E. C. D. S., Jia, J.-P., Lobo, V. J. S.-A., Megías, D., Felipe, I., et al. (2018) · Nature · doi:10.1038/nature25751 · Cited by 130 · see citing works
Deciphering the role of stroma in pancreatic cancer
Waghray, M., Yalamanchili, M., di Magliano, M. P., & Simeone, D. M. (2013) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e328363affe · Cited by 123 · see citing works
Xue, J., Nguyen, D. T., & Habtezion, A. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.08.051 · Cited by 115 · see citing works
Feng, D., Park, O., Radaeva, S., Wang, H., Yin, S., Kong, X., Zheng, M., Zakhari, S., Kolls, J. K., & Gao, B. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.3967 · Cited by 110 · see citing works
Spatial and phenotypic immune profiling of metastatic colon cancer
Lazarus, J., Maj, T., Smith, J. J., Lanfranca, M. P., Rao, A. U. K., D'Angelica, M. I., Delrosario, L., Girgis, A. A., Schukow, C. P., Shia, J., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.121932 · Cited by 108 · see citing works
Self-citationIL22RA1/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 99 · see citing works
Self-citationModel organoids provide new research opportunities for ductal pancreatic cancer
Boj, S. F., Hwang, C., Baker, L. A., Engle, D. D., Tuveson, D. A., & Clevers, H. C. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1014757 · Cited by 71 · see citing works
Protective and Pathological Properties of IL-22 in Liver Disease
Cobleigh, M. A., & Robek, M. D. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.08.043 · Cited by 69 · see citing works
Halbrook, C., Wen, H.-J., Ruggeri, J. M., Takeuchi, K. K., Zhang, Y.-Q., di Magliano, M. P., & Crawford, H. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.09.009 · Cited by 66 · see citing works
Self-citationWen, Z., Liao, Q., Zhao, J., et al. (2013) · Annals of Surgical Oncology · doi:10.1245/s10434-013-3322-x · Cited by 52 · see citing works
Xu, X., Tang, Y., Guo, S., Zhang, Y., Tian, Y., Ni, B., & Wang, H. (2014) · Pancreas · doi:10.1097/mpa.0000000000000055 · Cited by 37 · see citing works
Self-citationDevelopmental Pathways Direct Pancreatic Cancer Initiation from Its Cellular Origin
Reichert, M., Blume, K., Kleger, A., Hartmann, D., & von Figura, G. (2015) · Stem Cells International · doi:10.1155/2016/9298535 · Cited by 30 · see citing works
Epithelial-mesenchymal transition and pancreatic cancer progression
Dangi-Garimella, S. Y., Krantz, S. B., Shields, M. A., Grippo, P. J., & Munshi, H. G. (2012) · Europe PMC (PubMed Central) · Cited by 16 · see citing works
Tumor-Promoting Inflammatory Networks in Pancreatic Neoplasia: Another Reason to Loathe Kras
Vonderheide, R. H. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.04.020 · Cited by 15 · see citing works
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Yi, Z., Wei, S., Jin, L., Jeyarajan, S., Yang, J., Gu, Y., Kim, H. S., Schechter, S., Lu, S., Paulsen, M. T., et al. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.09.014 · Cited by 41 · see citing works
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- Authors
- Perusina Lanfranca, M., Zhang, Y., Girgis, A., Kasselman, S., Lazarus, J., Kryczek, I., Delrosario, L., Rhim, A., Koneva, L., Sartor, M., Sun, L., Halbrook, C., Nathan, H., Shi, J., Crawford, H. C., Pasca di Magliano, M., Zou, W., & Frankel, T. L.
- Affiliations
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Frankel, Timothy L.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 158
- Issue
- 5
- Pages
- 1417-1432.e11
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC7197347
- OpenAlex
- W2996536778
- Cited by
- 81
- References
- 43
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 19 · 2023: 16 · 2022: 13 · 2021: 11 · 2020: 7
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Michigan
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- IL-22, pancreatic ductal adenocarcinoma, pancreatitis, STAT3, JAK/STAT signaling, MEK signaling, tumor inflammation, lung metastasis, tumor suppressor
- MeSH terms
- Cell Plasticity, Interleukin-22, Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Humans, Interleukins, Male, Metaplasia, Nitriles, Pancreas, Pancreatic Neoplasms, Pancreatitis, Pyrazoles, Pyridones, Pyrimidines, Pyrimidinones, Signal Transduction, Survival Analysis, Receptors, Interleukin, Mice, Knockout, Carcinoma, Pancreatic Ductal, RNA, Small Interfering, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Janus Kinases, HEK293 Cells, Epithelial-Mesenchymal Transition, Acinar Cells
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