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Tetraspanin-6 antagonizes the release of exosomes by stimulating the lysosomal degradation of syntenin and syndecan-4

ABSTRACT: Exosomes, extracellular vesicles (EV) of endosomal origin, emerge as master regulators of cell-to-cell signaling in physiology and various systemic diseases. Exosomes are highly enriched in tetraspanins (TSPN) and syndecans (SDC), the latter occurring mainly in proteolytically-cleaved form, as membrane-spanning C-terminal fragments of the proteins. While both protein families are membrane scaffolds appreciated for their role in exosome formation, composition and activity, we currently ignore whether these work together to control exosome biology. Here we show that TSPN6, a poorly characterized tetraspanin, acts as a negative regulator of exosome release by supporting the lysosomal degradation of SDC4 and syntenin. In addition, we demonstrate that TSPN6 tightly associates with SDC4. Interestingly, TSPN6-dependent lysosomal degradation of syntenin strictly requires SDC4. TSPN6 also inhibits the shedding of the SDC4-ectodomain, mimicking the effects of matrix metalloproteinase inhibitors. Taken together our data identify TSPN6 as a regulator of the trafficking and processing of SDC4 and highlight an important physical and functional interconnection between these membrane scaffolds for the production of exosomes. These findings clarify our understanding of the molecular determinants governing EV formation and have potentially broad impact for EV-related biomedicine.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Jean-Paul BORG

PROVIDER: PXD014559 | Pride | 2020-02-12

REPOSITORIES: Pride

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			Action	DRS
	GFP_TSPN6_Rep0.raw	Raw
	GFP_TSPN6_Rep0_20181126032111.raw	Raw
	GFP_TSPN6_Rep0_20181126055702.raw	Raw
	GFP_TSPN6_Rep1.raw	Raw
	GFP_TSPN6_Rep1_20181117150715.raw	Raw

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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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Tetraspanin-6 antagonizes the release of exosomes by stimulating the lysosomal degradation of syntenin and syndecan-4

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