Journal
EMBO JOURNAL
Volume 37, Issue 15, Pages -Publisher
WILEY
DOI: 10.15252/embj.201798357
Keywords
Cre-LoxP; extracellular vesicles; intratumoral heterogeneity; intravital microscopy; signaling networks
Categories
Funding
- European Research Council [648804, InCeM 642866, CoMMiTMenT 602121]
- Dutch Organization of Scientific Research (NWO) [823.02.017]
- Cancer Genomics Netherlands
- Doctor Josef Steiner Foundation
- European Union's Horizon 2020 Research and Innovation Program Under the Marie Sklodowska-Curie grant [642866]
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Recent data showed that cancer cells from different tumor subtypes with distinct metastatic potential influence each other's 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 invivo 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.
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