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Mechanisms of nuclear content loading to exosomes
Akira Yokoi1, Alejandro Villar-Prados1,2, Paul Allen Oliphint3
1Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Science Advances
|December 5, 2019
Summary
Cancer cells release exosomes containing genomic DNA (gDNA) linked to micronuclei (MN). This study reveals MN interact with exosome precursors, impacting nuclear exosome (nExo) formation and offering potential cancer biomarker insights.
Area of Science:
- Cell Biology
- Cancer Research
- Biochemistry
Background:
- Exosomes, vesicles released by cells, contain diverse cargoes including proteins, small RNAs, and genomic DNA (gDNA).
- The mechanisms of nuclear content loading into exosomes (nExo) are not well understood, despite gDNA's presence suggesting nuclear origins.
- Micronuclei (MN) are indicators of genomic instability in cancer cells.
Purpose of the Study:
- To investigate the relationship between cancer cell micronuclei (MN) and the formation of nuclear exosomes (nExo).
- To understand the loading mechanisms of nuclear contents into exosomes.
- To explore the potential of nExos as cancer biomarkers.
Main Methods:
- Imaging flow cytometry was used to analyze exosome content.
- Cancer cell lines and patient-derived samples (blood, ascites) were utilized.
- Genotoxic drug treatments were applied in vitro and in vivo.
Main Results:
- Approximately 10% of exosomes from cancer cells contained nuclear material, compared to <1% from patient samples.
- Genotoxic drug treatment increased both MN and nExo formation.
- Multivesicular body precursors and tetraspanins were observed to interact directly with MN.
Conclusions:
- Micronuclei (MN) in cancer cells are associated with the formation of nuclear exosomes (nExo).
- Exosomal markers interact with MN, suggesting a mechanism for nuclear content incorporation.
- These findings provide novel insights into nExo biogenesis and their potential as cancer biomarkers.