Extracellular vesicle heterogeneity through the lens of multiomics

Silva, Taylon F. and Hutchins, Elizabeth and Zhao, Wenyan and Ciani, Yari and Kim, Minhyung and Ko, Emily and Mariscal, Javier and Qiu, Zhuyu and Bedier, Fatima and Kittel, Ágnes and Zhou, Bo and Wang, Yang and Hall, Megan and Galasso, Francesca and Reiman, Rebecca and Freeman, Michael R. and Parker, Sarah and Van Eyk, Jennifer and Yang, Wei and Posadas, Edwin and Guarnerio, Jlenia and Nolan, John and Théry, Clotilde and Zijlstra, Andries and Stott, Shannon and You, Sungyong and Demichelis, Francesca and Boutros, Paul C. and Van Keuren-Jensen, Kendall and Di Vizio, Dolores (2025) Extracellular vesicle heterogeneity through the lens of multiomics. CELL REPORTS MEDICINE, 6 (7). No. 102161. ISSN 2666-3791

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Abstract

Extracellular vesicles (EVs) are heterogeneous in size, biogenesis, content, and function. Aggressive cancer cells release a distinct, poorly characterized, and particularly large EV subtype, namely large oncosomes (LOs). This study employs an optimized method to improve LO yields and integrates mass spectrometry and RNA sequencing (RNA-seq) to profile their molecular cargo. A consistent set of proteins enriched in LOs is identified across glioma, prostate, and breast cancer cell lines. These proteins are also present as mRNA in LOs from the prostate cancer model and are abundant in plasma LOs from 20 patients with metastasis. Single-LO RNA-seq confirms bulk LO cargo, demonstrating the utility of single-cell technologies for large vesicle analysis. Our patient study provides proof-of-principle evidence that we can use multiomics to delve into EV heterogeneity, biogenesis, and composition. It also suggests that plasma LOs help stratify patients, supporting their potential prognostic value for developing a multi-analyte approach for liquid biopsy.

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