Pancreatic Cancer-Derived Extracellular Vesicles Enriched with miR-223-5p Promote Skeletal Muscle Wasting Associated with Cachexia.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) with cachexia-related muscle wasting as the main manifestation is associated with poor overall survival. Extracellular vesicles (EVs) are key mediators of inter-organ communication. Here, EVs and EV-microRNAs (miRNAs) are identified as mediate PDAC-skeletal muscle communication. EVs are isolated from PDAC patients, mouse models, patients-derived organoids, and mouse pancreatic cancer cells. Plasma-derived EVs from PDAC patients or mice are observed to remarkably induced muscle wasting in vitro and in vivo. Depletion of miRNA cargo in these EVs significantly alleviates their detrimental effects on skeletal muscles. Deep RNA sequencing is conducted to profile differentially expressed miRNAs in plasma EVs from patients with or without PDAC. The findings reveal that the expression of miR-223-5p expression in PDAC patients' plasma EVs is negatively associated with the 3-year overall survival. Mechanistic studies show that miR-223-5p contributes to reduced METTL14 transcription by targeting MAFA, associated with decreased m⁶A methylation in skeletal muscles and muscle wasting. This study highlights the absorption of miRNA in PDAC-derived EVs by skeletal muscles and reveals a previously unrecognized function of PDAC-derived EV-miR-223-5p in tumor-muscle inter-organ communication, offering novel insight into EV-miR-223-5p-based diagnostic and therapeutic strategies for PDAC patients with sarcopenia upon further validation.