2. Academic Validation
  3. Cancer-Associated Fibroblast-Secreted Exosomes Regulate Macrophage Polarization in Pancreatic Cancer via the NOD1 Pathway

Cancer-Associated Fibroblast-Secreted Exosomes Regulate Macrophage Polarization in Pancreatic Cancer via the NOD1 Pathway

  • J Biochem Mol Toxicol. 2025 Jan;39(1):e70126. doi: 10.1002/jbt.70126.
Wenxin Yang 1,  Yuanyuan Zheng 2,  Han Zhou 3,  Ruolong Liang 4,  Chaofeng Hu 5
Affiliations

Affiliations

  • 1 Department of Pathology, Guangdong Second Provincial General Hospital, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
  • 2 Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen, China.
  • 3 Department of Pathology, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen, China.
  • 4 Department of Pathology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
  • 5 Department of Pathology and Pathophysiology, School of Medicine, Jinan University, Guangzhou, China.
PMID: 39756063 DOI: 10.1002/jbt.70126
Abstract

Metastasis is a major cause of poor prognosis of pancreatic Cancer. Exosomes (Exos) regulate Cancer progression by modulating macrophage polarization. This study aimed to investigate the effects of cancer-associated fibroblast (CAF)-released Exos on macrophage polarization in pancreatic Cancer and the molecular mechanisms. THP-1 cells or xenografted tumor mice were treated with Exos from CAFs, and macrophage polarization was analyzed using quantitative Real-Time PCR (qPCR) and flow cytometry. THP-1 cells were cocultured with BXPC-3 cells, and metastasis was analyzed using Transwell assay and scratch test. Exosomal PTGS2 was detected using qPCR, and the NOD1 pathway was evaluated using western blot analysis. The results showed that Exos promoted M2-type polarization and inhibited M1-type polarization, and then facilitated pancreatic Cancer cell migration, invasion, and epithelial-mesenchymal transition. PTGS2 expression was increased in Exo-treated macrophages, and its knockdown in CAFs facilitated M2 to M1 macrophage polarization. Moreover, Exos promoted the NOD1 pathway via PTGS2, and inhibition of NOD1 reversed the polarization caused by Exos. Additionally, NOD1 was required in M1/M2 polarization in vivo mediated by Exos. In conclusion, CAF-secreted Exos facilitated M2 macrophage polarization by carrying PTGS2 to activate the NOD1 pathway, thereby promoting pancreatic Cancer metastasis, providing evidence that CAF-Exos accelerating pancreatic Cancer progression.

Keywords

NOD1 pathway; cancer‐associated fibroblast; exosome; macrophage polarization; pancreatic cancer.

Figures
Products