10 Extracellular vesicles that carry signalling networks drive phenocopying of migratory behaviour between cancer cells in vivo

Introduction Tumours consist of heterogeneous populations of cancer cells with various abilities to metastasize. Recent data shows that cancer cells from different subtypes exchange biomolecules through extracellular vesicles (EVs), influencing each other’s metastatic behaviour. How EVs can mediate this effect is still largely unknown, especially in tumours from the same subtype in which molecular differences are small but instrumental drivers of metastasis. Material and methods Here, we study EVs shed by two B16 melanoma lines with different metastatic potential. Using label-free tandem mass spectrometry and RNA sequencing we profile the tumour microenvironmental EVs shed by these clones in vivo. We use the Cre-LoxP system to monitor EV transfer in vivo in combination with intravital microscopy to study phenotypic changes induced by EV exchange. Results and discussions We show that melanoma cells with different metastatic capacities functionally exchange EVs in vivo. EVs shed into the tumour microenvironment by cancer cells contain interconnected protein and RNA signalling networks involved in a variety of processes, including cell migration. Transfer of EVs from highly metastatic and migratory cells copies their phenotype to other cancer cells. Conclusion We show that cancer cells influence each other’s behaviour in the tumour microenvironment through EVs. Profiling of tumor-derived EVs suggests that this is mediated by a diverse range of EV-molecules that together amplify numerous nodes of signalling networks in recipient cells.