Small extracellular vesicles (sEVs) mediate the interaction between tumor and tumor-associated macrophages (TAMs). This study aims to demonstrate that the pancreatic ductal adenocarcinoma (PDAC)-derived sEV Ezrin (sEV-EZR) could modulate macrophage polarization and promote PDAC metastasis. We isolated PDAC-derived sEVs and plasma sEVs from PDAC patients. Human blood mononuclear cell (PBMC)-derived macrophages were treated with PDAC-derived sEVs or the counterpart depleted Ezrin (EZR) with shRNA-mediated knockdown. We used enzyme-linked immunosorbent assays and flow cytometry to monitor macrophages polarization. NOD/SCID/IL2Rγ mice were treated with sEVs to study PDAC liver metastasis. The plasma sEV-EZR levels of 165 PDAC patients and 151 high-risk controls were analyzed. The EZR levels are higher in sEVs derived from PDAC cells and PDAC-patient plasma than that of the normal controls. PDAC-derived sEVs modulate the polarization of macrophages to M2 phenotype, while PDAC-shEZR-derived sEVs polarize macrophages into M1 phenotype. We found an increase in M1 TAMs and a decrease in M2 TAMs in orthotropic tumors treated with PDAC-shEZR-derived sEVs. The amount of liver metastasis in PDAC-shEZR-derived sEVs-treated mice was observed to be smaller than that of controls. The mean plasma sEV-EZR levels from PDAC patients were significantly higher than those from the controls (32.43±20.78 vs. 21.88±11.43 pg/ml; <0.0001). The overall survival in the high-plasma sEV-EZR patients was significantly shorter than that in the low-EZR group (6.94±15.25 vs. 9.63±15.11 months; =0.0418). sEV-EZR could modulate macrophage polarization and promote metastasis in PDAC. Targeting sEV-EZR can be considered a promising therapeutic strategy to inhibit PDAC metastasis.
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Int J Mol Sci
September 2023
Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs.
View Article and Find Full Text PDFAnal Methods
June 2022
ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), School of Natural Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW 2109, Australia.
Am J Cancer Res
January 2020
Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University Taipei, Taiwan.
Small extracellular vesicles (sEVs) mediate the interaction between tumor and tumor-associated macrophages (TAMs). This study aims to demonstrate that the pancreatic ductal adenocarcinoma (PDAC)-derived sEV Ezrin (sEV-EZR) could modulate macrophage polarization and promote PDAC metastasis. We isolated PDAC-derived sEVs and plasma sEVs from PDAC patients.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!