Cancer cells copy migratory behavior and exchange signaling networks via extracellular vesicles. (15th June 2018)

• Record Type: Journal Article
• Authors: Steenbeek, Sander C; Pham, Thang V; de Ligt, Joep; Zomer, Anoek; Knol, Jaco C; Piersma, Sander R; Schelfhorst, Tim; Huisjes, Rick; Schiffelers, Raymond M; Cuppen, Edwin; Jimenez, Connie R; van Rheenen, Jacco
• Is Part Of: EMBO journal. Volume 37:Number 15(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-06-15
• Subjects: Cre‐LoxP -- extracellular vesicles -- intratumoral heterogeneity -- intravital microscopy -- signaling networks; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798357
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Imaging microscopy in live animals combined with transcriptome–proteome analyses are used to characterize the function and content of extracellular vesicles (EVs) shed in vivo by mouse melanoma tumors with distinct metastatic potential. These data suggest that EVs promote cell migration by transferring clusters of RNA and proteins acting in the same physiological signaling networks. B16F1 and B16F10 melanoma cell clones with differential metastatic potencies functionally exchange EVs in vivo . The less metastatic B16F1 cells display increased invasive potential after uptake of EVs from the more aggressive B16F10 cells. EVs purified from B16F10 microenvironments contain more complex and distinct cargo networks of RNAs and proteins involved in cell migration than seen for B16F1. Abstract : Melanoma cell subclones adopt increased migratory behavior in vivo by extracellular vesicle uptake, amplifying signaling nodes involved in cell motility.