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Updated: Feb 24, 2026
Bioluminescent Orthotopic Model of Pancreatic Cancer Progression
Published on: June 28, 2013
c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice
Takeshi Sato1, Wataru Shibata1,2, Yohko Hikiba3
1Department of Gastroenterology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c-Jun N-terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1aCre/+ ;KrasG12D/+ mice with JNK1-/- mice to generate Ptf1aCre/+ ;KrasG12D/+ ;JNK1-/- (Kras;JNK1-/- ) mice. Tumor weight was significantly lower in Kras;JNK1-/- mice than in Kras;JNK1+/- mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1-/- mice. Tumor diameters were significantly smaller in JNK1-/- mice. Phosphorylated JNK (p-JNK) was activated in α-smooth muscle actin (SMA)-positive cells in tumor stroma, and mPC-conditioned medium activated p-JNK in tumor-associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8+ T-cell infiltration by recruitment of dendritic cells, and the number of CD8+ T cells was decreased in Kras;JNK1+/- mice compared with Kras;JNK1-/- mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8+ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8+ T cells, which would be expected to enhance antitumor immunity.
Insights
In pancreatic cancer, inhibiting c-Jun N-terminal kinase (JNK) in the tumor stroma may enhance antitumor immunity. Blocking JNK increases Ccl20 secretion, promoting CD8+ T cell infiltration and potentially improving therapeutic outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is aggressive with limited therapeutic options.
- The role of c-Jun N-terminal kinase (JNK) in PDAC stroma, characterized by desmoplasia, is poorly understood.
- JNK signaling may influence the tumor microenvironment and immune cell infiltration.
Purpose of the Study:
- To investigate the role of JNK in the pancreatic tumor stroma.
- To determine if JNK inhibition impacts tumor growth and immune cell infiltration in PDAC models.
- To explore JNK's effect on Ccl20 chemokine secretion by tumor-associated fibroblasts (TAFs).
Main Methods:
- Generated genetically engineered mouse models (Kras;JNK1-/-) by crossing PDAC models with JNK1-deficient mice.
- Transplanted murine PDAC cells into wild-type and JNK1-deficient mice.
- Analyzed tumor weight, dimensions, histology, and immune cell populations (CD8+ T cells); assessed phosphorylated JNK (p-JNK) and Ccl20 expression in vitro and in vivo.
Main Results:
- Tumor growth was significantly reduced in mice lacking JNK1.
- JNK activation was observed in α-SMA-positive stromal cells; PDAC-conditioned medium activated JNK in TAFs.
- JNK activation downregulated Ccl20 secretion from TAFs, correlating with decreased CD8+ T cell infiltration.
Conclusions:
- JNK signaling in the pancreatic tumor stroma promotes tumor growth and suppresses Ccl20 secretion.
- Inhibition of JNK in pancreatic tumor stroma could increase TAF-derived Ccl20 secretion.
- JNK inhibition may enhance antitumor immunity by promoting CD8+ T cell accumulation, representing a potential therapeutic strategy for PDAC.
