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Proteomics analyses TSPAN family proteins in cell and exosome

ABSTRACT: Exosome-based cell-free therapeutics has received increasing attention in recent decades. Due to the potential demand for therapeutic exosomes, appropriate methods for preservation and storage of exosomes are essential. Current cryopreservation strategies mostly focus on addition of cryoprotectants. However, due to the high concentration of cryoprotectant required, this approach can lead to unfavorable effects. Thus, other storage methods are urgently needed. In this study, we found that Tetraspanin 4 (TSPAN4) and other Tetraspanin family proteins play an essential role in protecting exosomes from cryo-damage. Moreover, we engineered TSPAN4-loaded exosomes which are resistant to cryo-damage. These engineered exosomes show similar properties to wild-type exosomes in protein composition, uptake by recipient cells, and cargo delivery efficiency. We believe our strategy of exosome cryopreservation, without the need for additional agents, will promote the clinical translation of exosomes as therapeutic agents.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Yang Chen

PROVIDER: PXD037947 | iProX | Thu Nov 03 00:00:00 GMT 2022

REPOSITORIES: iProX

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Project description:Background: Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA’s anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA’s anticancer action. Results: Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA’s anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. Conclusions: We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA’s anticancer action, further supporting its use in cancer therapy. Examination of small RNA populations in MCF7 cells and exosomes after DHA treatment.

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Proteomics analyses TSPAN family proteins in cell and exosome

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