Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors

• Published in: Cancer cell 2018-07, Vol.34 (1), p.119-135.e10
• Main Authors: Pavlyukov, Marat S., Yu, Hai, Bastola, Soniya, Minata, Mutsuko, Shender, Victoria O., Lee, Yeri, Zhang, Suojun, Wang, Jia, Komarova, Svetlana, Wang, Jun, Yamaguchi, Shinobu, Alsheikh, Heba Allah, Shi, Junfeng, Chen, Dongquan, Mohyeldin, Ahmed, Kim, Sung-Hak, Shin, Yong Jae, Anufrieva, Ksenia, Evtushenko, Evgeniy G., Antipova, Nadezhda V., Arapidi, Georgij P., Govorun, Vadim, Pestov, Nikolay B., Shakhparonov, Mikhail I., Lee, L. James, Nam, Do-Hyun, Nakano, Ichiro
• Format: Article
• Language: English
• Subjects: alternative splicing; Animals; apoptosis; Apoptosis - drug effects; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Communication; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1 - genetics; Cyclin D1 - metabolism; Drug Resistance, Neoplasm; extracellular vesicles; Extracellular Vesicles - drug effects; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Extracellular Vesicles - pathology; Female; glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; glioma; Humans; Mice, Inbred NOD; Mice, SCID; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; proneural-to-mesenchymal transition; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RNA Splicing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; spliceosome; Spliceosomes - drug effects; Spliceosomes - genetics; Spliceosomes - metabolism; Spliceosomes - pathology; Tumor Burden
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.05.012

Aggressive cancers such as glioblastoma (GBM) contain intermingled apoptotic cells adjacent to proliferating tumor cells. Nonetheless, intercellular signaling between apoptotic and surviving cancer cells remain elusive. In this study, we demonstrate that apoptotic GBM cells paradoxically promote proliferation and therapy resistance of surviving tumor cells by secreting apoptotic extracellular vesicles (apoEVs) enriched with various components of spliceosomes. apoEVs alter RNA splicing in recipient cells, thereby promoting their therapy resistance and aggressive migratory phenotype. Mechanistically, we identified RBM11 as a representative splicing factor that is upregulated in tumors after therapy and shed in extracellular vesicles upon induction of apoptosis. Once internalized in recipient cells, exogenous RBM11 switches splicing of MDM4 and Cyclin D1 toward the expression of more oncogenic isoforms. [Display omitted] •apoEVs promote a more aggressive and therapy-resistant phenotype of GBM•apoEVs are specifically enriched with spliceosomal proteins and snRNAs•apoEVs affect mRNA splicing in recipient GBM cells•RBM11 is partly responsible for apoEV-mediated phenotypic changes of recipient cells Pavlyukov et al. show that apoptotic GBM cells secrete vesicles enriched with components of spliceosomes to alter RNA splicing in surviving tumor cells and promote their aggressiveness. They identify RBM11 as one such factor that switches MDM4 and cyclinD1 toward the more oncogenic isoforms in recipient cells.