c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice

Takeshi Sato, Wataru Shibata, Yohko Hikiba, Yoshihiro Kaneta, Nobumi Suzuki, Sozaburo Ihara, Yasuaki Ishii, Soichiro Sue, Eri Kameta, Makoto Sugimori, Hiroaki Yamada, Hiroaki Kaneko, Tomohiko Sasaki, Tomohiro Ishii, Toshihide Tamura, Masaaki Kondo, Shin Maeda

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2156-2165
Number of pages10
JournalCancer Science
Volume108
Issue number11
DOIs
Publication statusPublished or Issued - Nov 2017

Keywords

  • Ccl20
  • JNK
  • Kras
  • molecular targeted therapy
  • pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this