Dataset Information

Circadian Regulation of Protein Cargo in Exosomes

ABSTRACT: The circadian clock controls many aspects of physiology, but it remains undescribed whether extracellular vesicles (including exosomes) involved in cell-cell communications between tissues are regulated in a circadian pattern. We demonstrate a 24 h rhythmic abundance of individual proteins in exosomes using liquid chromatography-mass spectrometry in circadian-synchronised tendon fibroblasts. Further, the release of exosomes enriched in RNA-binding proteins was temporally separated from those enriched in cytoskeletal and matrix proteins, which peaked during the end of the light phase. Finally, we targeted the protein sorting mechanism in the exosome biogenesis pathway and established (by knockdown of circadian-regulated flotillin-1) that matrix metalloproteinase 14 abundance in tendon fibroblast exosomes is under flotillin-1 regulation. In conclusion, we have identified proteomic time signatures for exosomes released by tendon fibroblasts which supports the view that the circadian clock regulates protein cargo in exosomes involved in cell-cell crosstalk.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Erwin Schoof

LAB HEAD: Michael Kjaer

PROVIDER: PXD022393 | Pride | 2022-05-19

REPOSITORIES: Pride

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Publications

Circadian regulation of protein cargo in extracellular vesicles.

Yeung Ching-Yan Chloé CC Dondelinger Frank F Schoof Erwin M EM Georg Birgitte B Lu Yinhui Y Zheng Zhiyong Z Zhang Jingdong J Hannibal Jens J Fahrenkrug Jan J Kjaer Michael M

Science advances 20220408 14

The circadian clock controls many aspects of physiology, but it remains undescribed whether extracellular vesicles (EVs), including exosomes, involved in cell-cell communications between tissues are regulated in a circadian pattern. We demonstrate a 24-hour rhythmic abundance of individual proteins in small EVs using liquid chromatography-mass spectrometry in circadian-synchronized tendon fibroblasts. Furthermore, the release of small EVs enriched in RNA binding proteins was temporally separated ...[more]

PMID: 35394844

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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.

Dataset Information

Circadian Regulation of Protein Cargo in Exosomes

Publications

Circadian regulation of protein cargo in extracellular vesicles.

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