1. Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors.
- Author
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Pavlyukov MS, Yu H, Bastola S, Minata M, Shender VO, Lee Y, Zhang S, Wang J, Komarova S, Wang J, Yamaguchi S, Alsheikh HA, Shi J, Chen D, Mohyeldin A, Kim SH, Shin YJ, Anufrieva K, Evtushenko EG, Antipova NV, Arapidi GP, Govorun V, Pestov NB, Shakhparonov MI, Lee LJ, Nam DH, and Nakano I
- Subjects
- Animals, Brain Neoplasms drug therapy, Brain Neoplasms genetics, 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 drug effects, Extracellular Vesicles genetics, Extracellular Vesicles pathology, Female, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma pathology, Humans, Mice, Inbred NOD, Mice, SCID, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phenotype, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, RNA Splicing, RNA-Binding Proteins genetics, Signal Transduction, Spliceosomes drug effects, Spliceosomes genetics, Spliceosomes pathology, Tumor Burden, Apoptosis drug effects, Brain Neoplasms metabolism, Extracellular Vesicles metabolism, Glioblastoma metabolism, RNA-Binding Proteins metabolism, Spliceosomes metabolism
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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