Macrophage-derived exosomal microRNAs promote metastasis in pancreatic ductal adenocarcinoma

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive disease that can metastasize to distant organs such as the lung and liver. However, the exact mechanisms underlying PDAC metastasis remain unclear. Tumor-associated macrophages (TAMs) have been shown to play a critical role in cancer initiation, progression, outgrowth, and metastasis, likely through their interaction with cancer cells via extracellular vesicles known as exosomes. However, the precise mechanisms of this interaction are not fully understood.

Methods: In this study, we obtained TAMs from PDAC patients and isolated exosomes from their culture medium. We characterized these exosomes and analyzed their miRNA expression profiles using Multiplex miRNA assays with FirePlex particle technology. Additionally, we conducted in vitro co-culture experiments between PDAC cells and conditioned media or exosomes from TAMs to investigate the crosstalk between these cells via exosomes. Furthermore, we evaluated the in vivo lung metastasis of PDAC cells treated with TAM-derived exosomes in athymic nude mice.

Results: TAMs from PDAC patients promoted the invasiveness and migratory potential of PDAC cells, partially through the effects of TAM-derived exosomes. Specifically, we identified two microRNAs, miR-202-5p and miR-142-5p, which were transferred from TAM-derived exosomes to PDAC cells, resulting in the suppression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and promoting their invasiveness and migratory potential. We also found that distal metastasis was increased in PDAC cells treated with TAM-derived exosomes, partially through miR-202-5p and miR-142-5p.

Conclusions: Exosomal transfer of miR-202-5p and miR-142-5p plays a significant role in conferring invasiveness and migratory potential to PDAC cells. Targeting exosome communication may represent a promising new therapeutic strategy for reducing cancer metastasis of PDACs.

Keywords: Cancer metastasis; Exosomes; Phosphatase and tensin homolog deleted on chromosome ten (PTEN); Tumor-associated macrophages (TAMs); miRNAs; pancreatic ductal adenocarcinoma (PDAC).