Mutant Isocitrate Dehydrogenase 1 Alters Extracellular Vesicle Secretion and Cargo Composition in Cellular Models

Mutant isocitrate dehydrogenase 1 (IDH1) mutations are associated with various types of adult gliomas and cancers. These mutations result in the production of D-2-hydroxyglutarate (D2HG), which leads to epigenetic changes. Recent research indicates that mutant IDH1 may also impact how tumor cells communicate via small extracellular vesicles (sEVs). Gliomas often have elevated levels of these sEVs, but the relationship between mutant IDH1 and sEV production/cargo composition is not fully understood.

In experiments using glioblastoma and chondrosarcoma cell models, researchers found that mutant IDH1 expression correlated with increased sEV secretion. Additionally, D2HG was found to be packaged within sEVs that were taken up by cells. When cell-permeable D2HG was administered, it led to a dose-dependent increase in sEV release from IDH1 wild-type cells.

Untargeted proteomics revealed that mutant IDH1 expression altered the cargo composition of sEVs in a cell type-specific manner. For instance, mutant chondrosarcoma sEVs were enriched in one-carbon metabolism enzymes, while mutant glioma sEVs contained lysosomal luminal proteins and endoplasmic reticulum (ER) chaperones. Transcriptomic analysis of mutant IDH1 glioma cells suggested an expanded ER folding capacity and reduced ribosomal pathways.

Notably, sEVs derived from mutant IDH1 glioma cells decreased nascent protein synthesis in IDH1 wild-type recipient cells. These findings collectively suggest that sEVs can act as carriers of mutant IDH1 phenotypes, potentially influencing how tumor cells communicate with their surrounding microenvironment.