Physical and Molecular Landscapes of Mouse Glioma Extracellular Vesicles Define Heterogeneity
Aron Gyuris,
Jose Navarrete-Perea,
Ala Jo,
Simona Cristea,
Shuang Zhou,
Kyle Fraser,
Zhiyun Wei,
Anna M. Krichevsky,
Ralph Weissleder,
Hakho Lee,
Steve P. Gygi,
Al Charest
Affiliations
Aron Gyuris
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Jose Navarrete-Perea
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA
Ala Jo
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Simona Cristea
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
Shuang Zhou
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Kyle Fraser
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Zhiyun Wei
Department of Neurology, Ann Romney Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Anna M. Krichevsky
Department of Neurology, Ann Romney Center for Neurologic Diseases, Initiative for RNA Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Ralph Weissleder
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Hakho Lee
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Steve P. Gygi
Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA
Al Charest
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Corresponding author
Summary: Cancer extracellular vesicles (EVs) are highly heterogeneous, which impedes our understanding of their function as intercellular communication agents and biomarkers. To deconstruct this heterogeneity, we analyzed extracellular RNAs (exRNAs) and extracellular proteins (exPTNs) from size fractionation of large, medium, and small EVs and ribonucleoprotein complexes (RNPs) from mouse glioblastoma cells by RNA sequencing and quantitative proteomics. mRNA from medium-sized EVs most closely reflects the cellular transcriptome, whereas small EV exRNA is enriched in small non-coding RNAs and RNPs contain precisely processed tRNA fragments. The exPTN composition of EVs and RNPs reveals that they are closely related by vesicle type, independent of their cellular origin, and single EV analysis reveals that small EVs are less heterogeneous in their protein content than larger ones. We provide a foundation for better understanding of segregation of macromolecules in glioma EVs through a catalog of diverse exRNAs and exPTNs. : Extracellular vesicles (EVs) are highly heterogeneous. Using genetically defined mouse glioblastoma tumor cells, Gyuris et al. employ a differential filtration approach to isolate EVs based on size and establish the differential distribution of RNA and protein between EVs and ribonucleoprotein complexes in genetically distinct contexts. Keywords: extracellular RNA, proteome, extracellular vesicles, exosomes, glioblastoma, mouse model
