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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Recent data showed that cancer cells from different tumor subtypes with distinct metastatic potential influence each other9s metastatic behavior by exchanging biomolecules through extracellular vesicles (EVs). However, it is debated how small amounts of cargo can mediate this effect, especially in tumors where all cells are from one subtype, and only subtle molecular differences drive metastatic heterogeneity. To study this, we have characterized the content of EVs shed in vivo by two clones of melanoma (B16) tumors with distinct metastatic potential. Using the Cre‐LoxP system and intravital microscopy, we show that cells from these distinct clones phenocopy their migratory behavior through EV exchange. By tandem mass spectrometry and RNA sequencing, we show that EVs shed by these clones into the tumor microenvironment contain thousands of different proteins and RNAs, and many of these biomolecules are from interconnected signaling networks involved in cellular processes such as migration. Thus, EVs contain numerous proteins and RNAs and act on recipient cells by invoking a multi‐faceted biological response including cell migration.

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.