Mechanisms of nuclear content loading to exosomes

• Published in: Science advances Vol. 5; no. 11; p. eaax8849
• Main Authors: Yokoi, Akira, Villar-Prados, Alejandro, Oliphint, Paul Allen, Zhang, Jianhua, Song, Xingzhi, De Hoff, Peter, Morey, Robert, Liu, Jinsong, Roszik, Jason, Clise-Dwyer, Karen, Burks, Jared K., O’Halloran, Theresa J., Laurent, Louise C., Sood, Anil K.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.11.2019
• Subjects: Biomarkers, Tumor - metabolism; Cancer; Cell Biology; Cell Line, Tumor; DNA - genetics; DNA Copy Number Variations - genetics; DNA Damage - drug effects; DNA Damage - genetics; Exosomes - metabolism; Female; Humans; Micronuclei, Chromosome-Defective; Ovarian Neoplasms - genetics; SciAdv r-articles; Tetraspanins - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aax8849

Nuclear-derived exosomes generated by micronuclear collapse provide an accurate snapshot of genomic features in ovarian cancer. Exosome cargoes are highly varied and include proteins, small RNAs, and genomic DNA (gDNA). The presence of gDNA suggests that different intracellular compartments contribute to exosome loading, resulting in distinct exosome subpopulations. However, the loading of gDNA and other nuclear contents into exosomes (nExo) remains poorly understood. Here, we identify the relationship between cancer cell micronuclei (MN), which are markers of genomic instability, and nExo formation. Imaging flow cytometry analyses reveal that 10% of exosomes derived from cancer cells and <1% of exosomes derived from blood and ascites from patients with ovarian cancer carry nuclear contents. Treatment with genotoxic drugs resulted in increased MN and nExos both in vitro and in vivo. We observed that multivesicular body precursors and exosomal markers, such as the tetraspanins, directly interact with MN. Collectively, this work provides new insights related to nExos, which have implications for cancer biomarker development.