Splicing Factors and Rna Processing Alternations: Exploring New Players in Glioblastoma Development

Glioblastoma multiforme (GBM) is a highly malignant brain tumor type with 14 months average patient survival, high incidence of recurrence and no effective line of treatment. Genomic analyses became an essential resource to understand the molecular alterations that cause cancer. In the case of GBM, analysis of hundreds of samples produced an extensive transcriptomic map, identified prevalent mutations and defined important tumor drivers. Unfortunately, clinical trials based on these results have not yet delivered positiv outcomes. Therefore, we make a case for investigating other regulatory routes known to promote tumor relapse and influence treatment response. Our application focus on splicing, a critical regulatory step in which RNAs are assembled into mature transcripts. RNA binding proteins (RBPs) function as core regulators of the splicing process. We recently conducted a functional screen with all 1,542 human RBPs and identified SNRPB, ETFTUD2 and MAGOH as potential novel players in glioblastoma development. Specific Aims. In Aim 1, we propose to generate splicing profile maps for glioblastoma and link them to biological processes and pathways relevant to GBM development. In Aim 2, we will investigate the possible roles of SNRPB, ETFUD2 and MAGOH in tumor initiation, chemo- and radio-resistance and determine the splicing events/genes under their influence. In Aim 3, we will bridge datasets to establish a direct correlation between these 3 proteins and splicing alterations in GBM. Finally, the most relevant splicing events/genes derived from this analysis will be investigated to determine their role in cancer tumor initiation and therapy resistance. PUBLIC HEALTH RELEVANCE: For numerous cancer types with no effective treatment and therefore extremely poor outcome, genomic analyses have become an important tool to identify new avenues for therapy. This is the case with glioblastoma multiforme (GBM), a highly malignant brain tumor with only 14 months average patient survival. Our major goal in this project is to use the power of genomics allied to robust biological validation to dissect the contribution of splicing to glioblastoma development. We will generate detailed splicing profile maps for glioblastoma and test our hypothesis that altered levels of SNRPB, MAGOH and EFTUD2 produce highly relevant splicing alterations that are often observed in GBMs and have significant contribution to tumor development.