Researchers have discovered distinct extracellular nanoparticles, termed supermeres, that have the potential to act as circulating biomarkers and therapeutic targets for a host of human diseases.
Extracellular vesicles (EVs) are lipid bound vesicles secreted by cells into the extracellular space. There are three main subtypes of EVs: microvesicles (MVs), exosomes and apoptotic bodies. The cargo of EVs consist of lipids, nucleic acids and proteins that are associated with the plasma membrane and cytosol as well as lipid metabolism.
Exosomes are endosome-derived, small EVs (sEVs) enclosed by a lipid bilayer. Recently, researcher identified a type of small non-membranous extracellular nanoparticle termed exomere. Both exosomes and exomeres are released by most cells and tissues under pathological conditions, and their production seems to be altered in several disease states including in neoplastic, cardiovascular, immunological and neurological disorders.
There is a growing interest in secreted EVs and exomere nanoparticles due to their sources of clinically relevant cargo. However, variable methods of isolation and their intrinsic heterogeneity pose major challenges to realising their clinical potential.
Recently, a team of researchers at Vanderbilt University Medical Center set out to provide a comprehensive proteomic and RNA analysis of clinically relevant cargo unique to exosomes and exomeres in a human colorectal cancer cell line, called DiFi. They used an optimised strategy to purify sEVs and a simplified method to isolate exomeres. But early on in their study, they discovered that the high-speed ultracentrifugation of the exomere supernatant resulted in a distinct extracellular nanoparticle that they termed supermere.
The researchers then began to explore supermeres further. Fluid-phase atomic force microscopy was used to determine that supermeres were morphologically and structurally distinct from exomeres. They also displayed different cellular-uptake kinetics than sEVs and exomeres in vitro, and exhibited a great uptake in vivo in all the examined tissues. Moreover, many of the clinically relevant proteins previously reported to be in exosomes, such as amyloid precursor protein (APP), cellular-mesenchymal-epithelial transition factor (MET), glypican 1 (GPC1), argonaute-2 (AGO2), TGFβ-induced (TGFBI), numerous glycolytic enzymes) and extracellular RNA (exRNA; miR-1246), were found to be highly enriched in supermeres.
Additionally, the team identified three functional properties of cancer-derived supermeres: (1) increased lactate secretion in recipient cells, (2) transfer of cetuximab resistance to cetuximab-sensitive cells and (3) altered liver metabolism following systemic injection. Moreover, mass spectrometry revealed that the most abundant protein in sEVs was DPEP1, which is a glycophosphatidylinositol (GPI)-linked dipeptidase that has been reported to be upregulated in colorectal adenomas and cancer.
Their findings, reported in Nature Cell Biology, act as a significant advancement in our understanding of the role of extracellular vesicles and nanoparticles in the shuttling of cargo between cells both in health and disease.
Clinical usefulness of extracellular nanoparticles
Overall, this study identifies a distinct functional nanoparticle that is morphologically and molecularly distinct from exosomes. Supermeres have the potential to act as circulating biomarkers and therapeutic targets for a host of human diseases. Furthermore, the researchers demonstrated the ability to isolate and measure the contents of distinct populations of sEVs and nanoparticles to assign cargo to their correct carriers. This is important and exciting because they have important implications for cancer, Alzheimer’s disease, heart disease and COVID-19 infection.
Robert Coffey, senior author of the paper, said:
“We’ve identified a number of biomarkers and therapeutic targets in cancer and potentially in a number of other disease states that are cargo in these supermeres. What is left to do now is to figure out how these things get released.”
Image credit: ETH Zurich