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Heterogeneity in extracellular vesicles (EVs). Various types of extracellular vesicles have been identified and characterized based on their mechanism of biogenesis and the presence of surface biomarkers. Three major classic types of EVs are listed here: 1) exosomes which are small sized EVs formed during the process of endosomal maturation. The key feature of their biogenesis is the formation of a multivesicular body (MVB) which contains small intraluminal vesicles that contain cargo of different types. The MVBs fuse with the plasma membrane and release intraluminal vesicles in the extracellular space as EVs. 2) Microvesicles which are characterized by large size are formed through the blebbing of plasma membrane. 3) Apoptotic bodies are formed by the cells actively undergoing cell death. Alongside these vesicles there are many others that have been identified with overlapping size and routes of biogenesis.
Background
Nearly all cells secrete small extracellular vesicles (EVs) that contain bioactive molecules, including miRNAs. Recently the Kasinski lab determined that cancer-cell-derived EVs can alter the phenotype of recipient cells and that the EV-encapsulated RNA is responsible for the majority of the phenotype observed (Scientific Reports, 2022). Since publishing this work, the lab has focused on identifying novel EV biogenesis pathways, and on understanding how cancer cells hijack EVs and load them with various miRNAs. To address this the lab sequenced miRNAs from EVs, and the cells that generated the EVs, and identified something unexpected. They found that a significant fraction of miRNAs reported as being depleted from tumor tissue are enriched, specifically in the EVs isolated from cancer cells, suggesting that tumors hijack EVs and actively load them with RNAs as a mechanism to disseminate them out of the tumor cell. She further identified a conserved five-nucleotide motif present in >75% of the miRNAs enriched in cancer-cell-derived EVs. This same motif was not abundant in RNAs harvested from the originating cells that produced the EVs nor in non-tumorigenic EVs. Dr. Kasinski hypothesizes that cancer cells are specifically using EVs as a mechanism to actively deplete themselves of particular RNAs. This finding has generated an intriguing, although perhaps not unexpected hypothesis, that an additional mechanism that cancer cells use to deplete themselves of large cohorts of miRNAs includes active loading of miRNAs into EVs.
Research Areas
Active loading of miRNAs into cancer-cell derived EVs:
The Kasinski lab identified a conserved five-nucleotide motif present in >75% of the miRNAs enriched in cancer-cell-derived EVs. This same motif was not abundant in RNAs harvested from the originating cells that produced the EVs nor in non-tumorigenic EVs. Dr. Kasinski hypothesizes that cancer cells are specifically using EVs as a mechanism to actively deplete themselves of particular RNAs. This finding has generated an intriguing, although perhaps not unexpected hypothesis, that an additional mechanism that cancer cells use to deplete themselves of large cohorts of miRNAs includes active loading of miRNAs into EVs. The lab is currently working to uncover the mechanisms in this process and to validate that the motif is both necessary and sufficeint for loading miRNAs into EVs.
Biogenesis:
In addition to identifying how specific RNAs are loaded into EVs, the Kasinski lab is also working on a novel EV biogenesis pathway. The canonical EV biogenesis pathway is via the endocytic pathway. Briefly, following endocytosis, the endosome inward buds, generating smaller vesicles inside of a larger vesicle, termed a multi vesicular body (MVB). The smaller vesicles are then released into the extracellular space after the MVB fuses with the plasma membrane. While this pathway is common for EV biogenesis, the lab recently determined that vesicles that bud off other organelles that can also generated MVBs. The lab determined that highly metastatic cancer cells shift to using these other pathways, and that EVs generated from these non-canonical pathways can promote an immune-cold tumor microenvironment.
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