Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways

S. Hallal, D. M. Mallawaaratchy, H. Wei, S. Ebrahimkhani, B. W. Stringer, B. W. Day, A. W. Boyd, G. J. Guillemin, M. E. Buckland, Kimberley L. Kaufman

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Abstract

The role of astrocytes is becoming increasingly important to understanding how glioblastoma (GBM) tumor cells diffusely invade the brain. Yet, little is known of the contribution of extracellular vesicle (EV) signaling in GBM/astrocyte interactions. We modeled GBM-EV signaling to normal astrocytes in vitro to assess whether this mode of intercellular communication could support GBM progression. EVs were isolated and characterized from three patient-derived GBM stem cells (NES + /CD133 + ) and their differentiated (diff) progeny cells (NES /CD133 ). Uptake of GBM-EVs by normal primary astrocytes was confirmed by fluorescence microscopy, and changes in astrocyte podosome formation and gelatin degradation were measured. Quantitative mass spectrometry-based proteomics was performed on GBM-EV stimulated astrocytes. Interaction networks were generated from common, differentially abundant proteins using Ingenuity® (Qiagen Bioinformatics) and predicted upstream regulators were tested by qPCR assays. Podosome formation and Cy3-gelatin degradation were induced in astrocytes following 24-h exposure to GBM-stem and -diff EVs, with EVs released by GBM-stem cells eliciting a greater effect. More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFβ1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR. Further qPCR studies identified significantly decreased Δ133p53 and increased p53β in astrocytes exposed to GBM-EVs that might indicate the acquisition of a pro-inflammatory, tumor-promoting senescence-associated secretory phenotype (SASP). Inhibition of TP53 and activation of MYC signaling pathways in normal astrocytes exposed to GBM-EVs may be a mechanism by which GBM manipulates astrocytes to acquire a phenotype that promotes tumor progression.

Original languageEnglish
Pages (from-to)4566-4581
Number of pages16
JournalMOLECULAR NEUROBIOLOGY
Volume56
Issue number6
DOIs
Publication statusPublished - Jun 2019
Externally publishedYes

Bibliographical note

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Keywords

  • Astrocytes
  • Extracellular vesicles
  • Glioblastoma stem-like cells
  • MYC
  • Podosome formation
  • Senescence-associated secretory phenotype
  • TP53

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    Hallal, S., Mallawaaratchy, D. M., Wei, H., Ebrahimkhani, S., Stringer, B. W., Day, B. W., Boyd, A. W., Guillemin, G. J., Buckland, M. E., & Kaufman, K. L. (2019). Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways. MOLECULAR NEUROBIOLOGY, 56(6), 4566-4581. https://doi.org/10.1007/s12035-018-1385-1