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EMBO J. 2018 Aug 1;37(15). pii: e98357. doi: 10.15252/embj.201798357. Epub 2018 Jun 14.

Cancer cells copy migratory behavior and exchange signaling networks via extracellular vesicles.

Author information

1
Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
2
Oncode Institute, Hubrecht Institute-KNAW & University Medical Centre Utrecht, Utrecht, The Netherlands.
3
OncoProteomics Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
4
Division Biomedical Genetics, Center for Molecular Medicine, Oncode Institute, University Medical Centre Utrecht, Utrecht, The Netherlands.
5
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
6
OncoProteomics Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands c.jimenez@vumc.nl j.v.rheenen@nki.nl.
7
Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands c.jimenez@vumc.nl j.v.rheenen@nki.nl.

Abstract

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 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.

KEYWORDS:

Cre‐LoxP; extracellular vesicles; intratumoral heterogeneity; intravital microscopy; signaling networks

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