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Cancer Cell. 2018 Jul 9;34(1):119-135.e10. doi: 10.1016/j.ccell.2018.05.012. Epub 2018 Jun 21.

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

Author information

1
Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, USA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation.
2
Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, USA; Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
3
Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, USA.
4
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation; Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow 119435, Russian Federation.
5
Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
6
Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, USA; Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430073, China.
7
Department of Mechanical Engineering, Ohio State University, Columbus, OH 43210, USA.
8
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
9
Department of Neurosurgery, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
10
Division of Animal Science, Chonnam National University, Gwangju 61186, Republic of Korea.
11
Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
12
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russian Federation; Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow 119435, Russian Federation.
13
Faculty of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russian Federation.
14
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation; Peoples' Friendship University of Russia, Moscow 117198, Russian Federation.
15
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russian Federation.
16
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russian Federation.
17
Department of Mechanical Engineering, Ohio State University, Columbus, OH 43210, USA; Department of Chemical and Biomolecular Engineering, Ohio State University, Columbus, OH 43210, USA.
18
Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; Department of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul 06351, Korea.
19
Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: inakano@uabmc.edu.

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.

KEYWORDS:

alternative splicing; apoptosis; extracellular vesicles; glioblastoma; glioma; proneural-to-mesenchymal transition; spliceosome

PMID:
29937354
PMCID:
PMC6048596
DOI:
10.1016/j.ccell.2018.05.012
[Indexed for MEDLINE]
Free PMC Article

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