Editors' ChoiceCancer

Glioblastoma cells feed off injury

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Science Translational Medicine  04 Jul 2018:
Vol. 10, Issue 448, eaau1971
DOI: 10.1126/scitranslmed.aau1971

Abstract

Apoptotic tumor cells in glioblastoma confer increased aggressiveness and therapy resistance among remaining cells.

Despite decades of research, glioblastoma (GBM) is characterized by poor outcome, with average survival of 15 months following maximal therapy. A central barrier to improving prognosis is the tendency of GBM cells to shift to more malignant and therapy-resistant phenotypes following standard therapies. Here, Pavlyukov et al. hypothesized that apoptotic GBM cells (representing up to 70% of tumor cells) could alter surviving tumor cell behavior through release of extracellular vesicles (apoEVs).

The authors first demonstrate that radiation-induced apoptotic cells, when mixed with untreated GBM cells, result in increased GBM invasion and growth, as well as decreased survival of mice with implanted tumors. Similar results were obtained incubating GBM cells with media derived from apoptotic cells. Nanoparticle tracking analysis revealed significant increase in extracellular vesicles (apoEVs) shed into media from GBM cells after induction of apoptosis. Tumor cells exposed to the ApoEVs showed significant increases in resistance to common GBM therapies such as temozolomide, cisplatin (CP), and radiation (6 to 12 Gy).

Analysis of the content of apoEVs revealed the presence of multiple spliceosomal proteins. Using fluorescence imaging, the authors showed that during tumor apoptosis, these proteins translocated from nucleus to cytoplasm. ApoEVs were further noted to induce global gene expression changes in GBM cells mirroring splicing changes noted in the most aggressive (mesenchymal) GBM subgroup. The authors then identified the RNA binding motif protein 11 (RBM11) as a candidate splicing factor, expressed in GBM cells upon apoptosis. RBM11, unsurprisingly, was encapsulated in apoEVs, and uptake of RBM11 was associated with tumor aggressiveness. Up-regulation of RBM11 modulated the splicing of MDM4 and cyclin (apoptotic and cell regulators, respectively) toward isoforms associated with poor patient outcomes.

The tendency of glioblastoma to increase growth with treatment is a frustrating challenge. The authors found a mechanism that may contribute to this phenomenon, via intercellular transfer of spliceosomal proteins from apoptotic to surviving cells. Although further studies using in vivo models are needed, the data shown here suggest that therapeutic strategies targeting apoEVs might improve the efficacy of conventional therapies.

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