Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors.
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, Nakano I
Cancer Cell 34 119-135.e10 01/09/2018
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.Full Text