Mechanisms of nuclear content loading to exosomes

Abstract

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.

Exosomal miRNAs in tumor microenvironment

“…The sorting of miRNAs to ILV may also require hydrophobic modification and GGAG base sequence at 3 ′ end of the miRNAs. This indicates that the 3 'ends of miRNAs may be involved in directing miRNAs into exosomes [83,84]. Finally, there are reports that Argonaute proteins (functional carriers of miRNAs) are related to the selection of exosomal miRNAs.…”

Tumor microenvironment complexity and therapeutic implications at a glance

“…In the context of cancer, they are involved in horizontal gene transfer and oncogenic transformation of normal cells as well as in the metastasis development [197]. Although there is no clear mechanistic evidence for their oncogenic potential, several proposals include (ii) overexpression of several pro-metastatic genes through the tolllike receptor 9 (TLR9)/ myeloid differentiation primary response 88 (MYD88) independent pathway [198]; (ii) transposable elements [199] and finally the cellular uptake of exosomes [200,201]. Another consequence of cell-free contacts involving cfDNA is the increased chemo-, radioresistance of cancer cells, as radiotherapy produces oxidized DNA which triggers reactive oxygen species and induces DNA damage response pathways [202].…”

Intercellular telomere transfer extends T cell lifespan

“…Using a side scatter threshold and calibration beads ( Extended Data Fig. 3c ) 9, 10 , we successfully excluded aggregates and visualized PKH67 + TelC + telomere vesicles within ∼10% of the total APC single particle vesicle fraction ( Extended Data Fig. 3d ).…”