PDTM-02. STRESS GRANULES ARE INDUCED BY OXIDATIVE STRESS IN PEDIATRIC BRAIN TUMORS AND PREDICT POOR OUTCOME

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 20; no. suppl_6; pp. vi203 - vi204
• Main Authors: Delaidelli, Alberto, Luca Negri, Gian, Cho, Brian, Minaker, Sean, El Naggar, Amal, Hukin, Juliette, Yip, Stephen, Santi, Mariarita, Maris, John, Sorensen, Poul
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 05-11-2018
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy148.844

Abstract
BACKGROUND/OBJECTIVES: Brain tumors represent the most common and aggressive pediatric cancer type, underscoring a dire need for novel therapeutic approaches. Tumors are continually exposed to acute changes in their microenvironment, including oxidative stress. To overcome acute stress, cells form stress granules (SGs), clusters of RNA and RNA-binding proteins (RBPs) that rapidly alter the cellular mRNA translation landscape. Preliminary data indicate that pharmacological inhibition of SG formation blocks the antioxidant response of the transcription factor NRF2 (NFE2L2), impairing pediatric sarcoma invasive and metastatic capacity. We therefore set out to determine if pediatric brain tumors rely on SGs to overcome oxidative stress, and if targeting SGs could represent a therapeutic approach for these tumors.
METHODS
We analyzed public databases for links between mRNA expression of the RBP G3BP1 and NFE2L2. Immunohistochemistry (IHC) for G3BP1, NRF2 and oxidative stress markers (4HNE) was performed on atypical theratoid rabdoid tumor (AT/RT), pediatric glioblastoma (pGBM) and ependymoma (EPN) tissue microarrays. AT/RT, pGBM and EPN cell lines were treated with NaAsO2 and H2O2 to induce oxidative stress and SG presence was determined by ImmunoFluorescence for the RBPs G3BP1 and TIA-1.
RESULTS
G3BP1 and NFE2L2 expression positively correlates in several pediatric tumor cohorts, including AT/RT, pGBM and EPN (p<0.01). IHC not only confirmed mRNA results, but revealed that G3BP1 over-expression is linked to higher WHO grade and recurrent disease in EPN. High G3BP1 levels are also predictive of poor outcome in pGBM (p<0.05). Finally, oxidative stress induces the RBPs G3BP1 and TIA-1 to form SGs in vitro. CONCLUSIONS: SGs represent an important mediator for the adaptive response of pediatric brain tumors to acute oxidative stress. Inhibiting SG formation might therefore constitute a therapeutic approach for AT/RT, pGBM and EPN. Future studies will aim at confirming the efficacy of drugs that inhibit SG formation in pediatric brain tumors.