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RNA Biol. 2017 Mar 4;14(3):305-316. doi: 10.1080/15476286.2016.1259061. Epub 2016 Nov 18.

High-throughput sequencing of two populations of extracellular vesicles provides an mRNA signature that can be detected in the circulation of breast cancer patients.

Conley A1, Minciacchi VR1,2,3,4, Lee DH1,2,3,4, Knudsen BS1,2, Karlan BY3,5, Citrigno L4,6, Viglietto G6, Tewari M7,8,9,10,11, Freeman MR1,3,4,12,13, Demichelis F14,15, Di Vizio D1,2,3,4,12,13.

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a Department of Biomedical Sciences , Cedars-Sinai Medical Center , Los Angeles , CA , USA.
b Department of Pathology and Laboratory Medicine , Cedars-Sinai Medical Center , Los Angeles , CA , USA.
c Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles , CA , USA.
d Department of Surgery , Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center , Los Angeles , CA , USA.
e Women's Cancer Program and Division of Gynecologic Oncology Obstetrics and Gynecology, Cedars-Sinai Medical Center , Los Angeles , CA , USA.
f Department of Experimental and Clinical Medicine , University Magna Graecia , Catanzaro , Italy.
g Department of Internal Medicine , University of Michigan , Ann Arbor , MI , USA.
h Department of Biomedical Engineering , University of Michigan , Ann Arbor , MI , USA.
i Biointerfaces Institute, University of Michigan , Ann Arbor , MI , USA.
j Center for Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor , MI , USA.
k Comprehensive Cancer Center, University of Michigan , Ann Arbor , MI , USA.
l The Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School , Boston , MA , USA.
m Department of Medicine , University of California , Los Angeles , USA.
n Centre for Integrative Biology, University of Trento , Trento , Italy.
o Institute for Precision Medicine, Weill Cornell Medicine , New York NY , USA.


Extracellular vesicles (EVs) contain a wide range of RNA types with a reported prevalence of non-coding RNA. To date a comprehensive characterization of the protein coding transcripts in EVs is still lacking. We performed RNA-Sequencing (RNA-Seq) of 2 EV populations and identified a small fraction of transcripts that were expressed at significantly different levels in large oncosomes and exosomes, suggesting they may mediate specialized functions. However, these 2 EV populations exhibited a common mRNA signature that, in comparison to their donor cells, was significantly enriched in mRNAs encoding E2F transcriptional targets and histone proteins. These mRNAs are primarily expressed in the S-phase of the cell cycle, suggesting that they may be packaged into EVs during S-phase. In silico analysis using subcellular compartment transcriptome data from the ENCODE cell line compendium revealed that EV mRNAs originate from a cytoplasmic RNA pool. The EV signature was independently identified in plasma of patients with breast cancer by RNA-Seq. Furthermore, several transcripts differentially expressed in EVs from patients versus controls mirrored differential expression between normal and breast cancer tissues. Altogether, this largest high-throughput profiling of EV mRNA demonstrates that EVs carry tumor-specific alterations and can be interrogated as a source of cancer-derived cargo.

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