Pleural Mesothelioma Extracellular Vesicles Reprogram Tumor Fibroblasts

Pleural Mesothelioma Extracellular Vesicles Reprogram Tumor Fibroblasts

by

Extracellular Vesicles Drive Tumor Progression

Pleural mesothelioma-derived extracellular vesicles carry distinct microRNA cargoes that reprogram fibroblasts in the tumor microenvironment, altering epigenetic regulation and promoting cancer cell proliferation, according to a study.

Pleural mesothelioma remains an aggressive malignancy characterized by notoriously low survival rates, prompting ongoing research into the fundamental mechanisms of disease pathogenesis to aid future therapeutic development. The study investigated the microRNA (miRNA) cargo found within extracellular vesicles (EVs) shed by pleural mesothelioma cells and tracked how these molecular packages affect fibroblasts, which serve as the predominant cell type inside the tumor microenvironment.

Profiling Distinct Subtype Signatures

High-throughput profiling revealed that extracellular vesicles derived from epithelioid and non-epithelioid mesothelioma subtypes carry distinct miRNA signatures. These cargoes differ significantly from one another as well as from non-malignant control samples. The data indicate that oncogenic miRNAs are upregulated within these vesicles, while tumor-suppressive miRNAs are downregulated. Researchers also identified specific miRNAs exclusive to either the epithelioid or non-epithelioid subtypes, pointing toward potential biomarkers that could eventually assist clinicians in distinguishing between subtypes and guiding treatment decisions.

Cell cycle growth mitosis synthesis division stages outline diagram cell cycle growth mitosis synthesis division stages

Cellular Response and Pathway Enrichment

To understand the downstream cellular response, the study treated isolated fibroblasts with these extracellular vesicles and conducted subsequent RNA sequencing and molecular analyses. An integrative miRNA-mRNA analysis predicted that the differential cargo modifies multiple pathways in the recipient fibroblasts. Gene Set Enrichment Analysis (GSEA) on human KEGG 2021 and oncogenic signatures indicated the upregulation of pathways involving the Cell Cycle, Neutrophils and Extracellular Trap Formation, alongside EZH2-regulated pathways.

Inflammatory CAF Phenotype and Oncogenic Signaling

Molecular evaluations confirmed that treated fibroblasts developed a predominant inflammatory cancer-associated fibroblast (CAF) phenotype. This shift showed increased levels of established markers such as IL-6, IL-8, MMP-1, MMP-3, ICAM1, ENG, and RRAGD. Alongside inflammation, researchers observed enhanced oncogenic signaling marked by elevated levels of Osteopontin, thrombospondin, Cystatin C, autotaxin, AXL, and ERBB2.

Epigenetic Alterations and Fibroblast Reprogramming

The study further demonstrated that these vesicles alter epigenetic regulation by modifying EZH2 phosphorylation at Thr345. Specifically, extracellular vesicles from epithelioid mesothelioma increased p-EZH2 levels, whereas non-epithelioid vesicles decreased them. Together, these alterations drive fibroblast reprogramming that subsequently enhances both migration and proliferation in pleural mesothelioma cells, establishing a supportive niche for tumor progression.

Keep reading

Read next