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

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. © 2018 Elsevier Inc.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.

Pavlyukov M.S.1, 3 , Yu H.1, 6 , Bastola S.1 , Minata M.1 , Shender V.O.3, 16 , Lee Y.12, 13 , Zhang S.1, 17 , Wang J.1, 6 , Komarova S.1 , Wang J.1, 6 , Yamaguchi S.1 , Alsheikh H.A.1 , Shi J.4 , Chen D.5 , Mohyeldin A.7 , Kim S.-H.11 , Shin Y.J.12 , Anufrieva K.3, 16, 15 , Evtushenko E.G.8 , Antipova N.V. 3, 9 , Arapidi G.P.3, 15 , Govorun V.3, 16 , Pestov N.B.3 , Shakhparonov M.I.3 , Lee L.J.4, 10 , Nam D.-H.12, 13, 14 , Nakano I.1, 2
Cell Press
Номер выпуска
  • 1 Department of Neurosurgery, University of Alabama at Birmingham, Wallace Tumor Institute, 410F, 1720 2nd Avenue S, Birmingham, AL 35294-3300, United States
  • 2 Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, United States
  • 3 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russian Federation
  • 4 Department of Mechanical Engineering, Ohio State University, Columbus, OH 43210, United States
  • 5 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, United States
  • 6 Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
  • 7 Department of Neurosurgery, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, United States
  • 8 Faculty of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russian Federation
  • 9 Peoples’ Friendship University of Russia, Moscow, 117198, Russian Federation
  • 10 Department of Chemical and Biomolecular Engineering, Ohio State University, Columbus, OH 43210, United States
  • 11 Division of Animal Science, Chonnam National University, Gwangju, 61186, South Korea
  • 12 Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
  • 13 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
  • 14 Department of Health Science & Technology, Samsung Advanced Institute for Health Science & Technology, Sungkyunkwan University, Seoul, 06351, South Korea
  • 15 Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russian Federation
  • 16 Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow, 119435, Russian Federation
  • 17 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430073, China
Ключевые слова
alternative splicing; apoptosis; extracellular vesicles; glioblastoma; glioma; proneural-to-mesenchymal transition; spliceosome
Дата создания
Дата изменения
Постоянная ссылка

Другие записи