Abstract
Exosomes support cell‐to‐cell communication in physiology and disease, including cancer. We currently lack tools, such as small chemicals, capable of modifying exosome composition and activity in a specific manner. Building on our previous understanding of how syntenin, and its PDZ partner syndecan (SDC), impact on exosome composition we optimized a small chemical compound targeting the PDZ2 domain of syntenin. In vitro , in tests on MCF‐7 breast carcinoma cells, this compound is non‐toxic and impairs cell proliferation, migration and primary sphere formation. It does not affect the size or the number of secreted particles, yet it decreases the amounts of exosomal syntenin, ALIX and SDC4 while leaving other exosomal markers unaffected. Interestingly, it also blocks the sorting of EpCAM, a bona fide target used for carcinoma exosome immunocapture. Our study highlights the first characterization of a small pharmacological inhibitor of the syntenin‐exosomal pathway, of potential interest for exosome research and oncology.
Highlights
It is clear that cells communicate via the release of membrane-limited vesicles, collectively called extracellular vesicles (EVs) (Kalluri & Lebleu, 2020; Mathieu, Martin-Jaular; Lavieu, & Théry, 2019; Stahl & Raposo, 2019)
We provide evidence that this inhibitor markedly affects the loading of exosomes with EpCAM, a transmembrane glycoprotein involved in cell migration, adhesion, proliferation and differentiation, which has been associated with the processes of tumorigenesis and metastasis of several carcinomas (Keller, Werner, & Pantel, 2019)
The search strategy for PDZ2 syntenin inhibitors was based on the PDZ targeted library developed from Enamine compound collection
Summary
It is clear that cells communicate via the release of membrane-limited vesicles, collectively called extracellular vesicles (EVs) (Kalluri & Lebleu, 2020; Mathieu, Martin-Jaular; Lavieu, & Théry, 2019; Stahl & Raposo, 2019). EVs represent complex biological messengers, containing lipids, proteins, and nucleic acids, including miRNAs. EVs appear to be important in various physiopathological situations, in particular during cancer progression, with a role in metastatic niche formation and tumour immune escape (Greening, Gopal, Xu, Simpson, & Chen, 2015; Wortzel, Dror, Kenific, & Lyden, 2019). EVs appear to be important in various physiopathological situations, in particular during cancer progression, with a role in metastatic niche formation and tumour immune escape (Greening, Gopal, Xu, Simpson, & Chen, 2015; Wortzel, Dror, Kenific, & Lyden, 2019) Their use for biomarker discovery, and as vehicles or targets of therapies is currently the focus of intense research. Exosomes are ‘exocytic’ vesicles, approximately 40–100 nm in size, released from most cell types Their biogenesis starts by the inward budding of the limiting membrane of endosomes, generating multivesicular endosomes. ‘Cancer exosomes’ are gaining considerable attention, in basic and applied clinical research, for their role in the modulation of the tumour microenvironment and their contribution to tumourhost crosstalk
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