Targeting RNA Splicing in Glioma

RNA alternative splicing (AS) is an evolutionally conserved co-transcriptional process, regulates transcriptome and proteome landscapes in eukaryotes, and in human diseases such as cancer. Unlike the numerous studies that have been conducted for characterizing glioma genomes, transcriptomes, methylomes, and proteomes, little has been done to associate glioma driver mutations with AS programs and evaluate the impact of dysregulated AS on cancer malignancy. Our analyses of AS in three glioma patient RNA-seq datasets indicate two AS glioma subtypes that show associations with WHO tumor grade, glioma driver mutations, and patient prognosis. Utilizing a human induced pluripotent stem cell (hiPSC)-derived glioma “avatar” model and clinical glioma models, we show that IDH1R132H/WT or PTEN-/-/CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII genotypes influence subtype-associated AS programs. Two subsets of RBPs that affect RNA splicing are differentially associated with these two AS glioma subtypes. Expression of subtype-associated RBPs or AS isoforms also affected AS events and growth of glioma stem-like cells (GSCs). In this research project, we plan to leverage our previous contributions, existing research program, recent findings, newly established glioma avatar models, cutting-edge CRISPR editing technology, and outstanding scientific premise to study whether glioma mutations influence AS programs and how RNA binding proteins (RBPs) and AS gene isoforms contribute to glioma tumor biology. AS programs will also be exploited for therapeutic intervention in treating gliomas. This project will address key gaps in our understanding of the relationships between glioma driver mutations and tumor-associated AS programs, and test whether targeting RNA splicing constitutes a therapeutic vulnerability to treat gliomas. In addressing these knowledge gaps this research will influence our understanding and treatment of glioma, and in so doing will likely influence the study of other cancers.