In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior

Summary

Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior.

Graphical Abstract

Highlights

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  Visualization of extracellular vesicle exchange between tumor cells in living mice

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  Direct in vivo evidence of local and systemic mRNA exchange between tumor cells

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  The exchange of biomolecules is mediated through extracellular vesicles

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  Metastatic behavior can be phenocopied through extracellular vesicle exchange

Abstract

Intravital imaging experiments reveal the extracellular vesicle-mediated exchange of molecules important for metastasis between tumor cells in living mice. This exchange results in metastatic properties being conferred to the receiving cell.