Translational mRNA Profiling Analysis of Pseudopalisading Cells in Bevacizumab Resistance of GBM

Abstract

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis that easily recurs. The antiangiogenic agent bevacizumab is used to treat recurrent GBM. However, GBM treated with bevacizumab easily rebounds due to evasive mechanisms that induce resistance to treatment, such as hypoxia-inducible factor (HIF) associated pathways. The transcription factor HIFs are oxygen-dependent and are degraded via the ubiquitin-dependent proteasomal pathway. Therefore, it is necessary to study bevacizumab resistance with HIF-associated pathways through translational mRNA profiling. This work applies a hypoxia response element (HRE) promoter to the ribosome affinity purification (TRAP) system for hypoxia-specific translational mRNA profiling analysis. Here, this work analyzes the translatome of pseudopalisading cells in the brain samples of orthotopic mouse models using hypoxia-responsive 5× HRE-TRAP system to investigate the molecular mechanism of drug resistance on pseudopalisading cells around the necrotic area induced by bevacizumab resistance. The translatomic analysis result shows that pseudopalisading cells exhibit notable enrichment of gene sets associated with neurodegenerative diseases, such as Alzheimer's disease. The outcomes of this study enhance clinical relevance, meaning that the translatomic analysis result of pseudopalisading cells during bevacizumab treatment-induced resistance provides new insight into a promising approach for developing targeted therapeutics. © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.