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Oncogenic Kras Activates a Hematopoietic-to-Epithelial IL-17 Signaling Axis in Preinvasive Pancreatic Neoplasia
Open accessAbstract
Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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“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 [188]
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Immunity, Inflammation, and Cancer
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Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
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Dynamics of the immune reaction to pancreatic cancer from inception to invasion
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Yang, X., Tao, X., Qi, W., Luo, R., Lan, T., Xie, K., Cai, Y., Gao, F., Lv, Y., Liu, C., et al. (2026) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2026.101718
Henderson, E. A., Łukomski, S., & Boone, B. A. (2026) · Technology in Cancer Research & Treatment · doi:10.1177/15330338261470694
Xing, S., 张佳宇, Wang, S., Hao, Y., Huang, D., Hao, M., Bao, W., Qu, X., Chi, Y., & Li, X. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1923822
García-Gómez, J., Agredano-Pérez, S., Rubio-Delgado, D. A., Aguilar‐Lemarroy, A., Jave‐Suárez, L. F., Guevara-Hernández, S. N., Bravo‐Cuéllar, A., Méndez-Clemente, A. S., Hernández‐Flores, G., & Villaseñor-Garcı́a, M. M. (2026) · Biomolecules · doi:10.3390/biom16101492
Metadata
- Authors
- McAllister, F., Bailey, J. M., Alsina, J., Nirschl, C. J., Sharma, R., Fan, H., Rattigan, Y., Roeser, J. C., Lankapalli, R. H., Zhang, H., Jaffee, E. M., Drake, C. G., Housseau, F., Maitra, A., Kolls, J. K., Sears, C. L., Pardoll, D. M., & Leach, S. D.
- Affiliations
- Johns Hopkins University (US)
- Children's Hospital of Pittsburgh (US)
- Corresponding author
- Leach, Steven D.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 25
- Issue
- 5
- Pages
- 621-637
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4072043
- OpenAlex
- W2085605492
- Cited by
- 405
- References
- 63
- Citations by year
- 2026: 21 · 2025: 27 · 2024: 39 · 2023: 37 · 2022: 43 · 2021: 38 · 2020: 44 · 2019: 37 · 2018: 15 · 2017: 32 · 2016: 29 · 2015: 29 · 2014: 14
- FWCI
- 16.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amgen
- National Cancer Institute (P01CA134292, T32CA126607, F32CA157044)
- National Institute of General Medical Sciences (T32GM066691)
- National Institute of Allergy and Infectious Diseases (T32AI007247)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097087)
- National Center for Research Resources (S10RR017933)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- KRAS G12D, IL-17 signaling, pancreatic intraepithelial neoplasia, chronic pancreatitis, IL-17 receptor, pancreatic stroma, chronic inflammation, IL-17 inhibition
- MeSH terms
- Animals, Carcinoma in Situ, Cell Transformation, Neoplastic, Epithelial Cells, Hematopoietic System, Humans, Inflammation, Mice, Transgenic, Pancreas, Pancreatic Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Receptors, Antigen, T-Cell, gamma-delta, Chemoprevention, Interleukin-17, Mice, Receptors, Interleukin-17, Th17 Cells
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