PATH-24. Understanding the RNA-regulatory interactome landscape of glioma treatment response

Abstract Deregulation of gene expression is a hallmark of cancer, underlying the phenotypic changes fundamental to tumorigenesis and cancer progression. This multi-step process is controlled at different levels, from transcription, RNA localization, stability and translation up to posttranslational protein modifications and protein degradation. Posttranscriptional gene regulation (PTGR) has been indicated as a key determinant of aberrant protein abundance, yet to what extent cancer cells alter system-wide PTGR control remains poorly understood. Nonetheless, it is clear that RNA does not only serve as an intermediate molecule towards protein expression, but can be a highly versatile molecule with critical regulatory functions. These functions are executed through interactions between RNA-binding proteins (RBPs) that interact with their respective target RNAs (RNA-interactome) to control all facets of PTGR, including RNA biogenesis, editing, splicing, localization, and translation. In this project, we aim to elucidate the RNA-interactome of several glioma subtypes and their dynamics under treatment, focused on the highly aggressive glioblastoma (GB). GB is the most common malignant primary brain tumour in adults, with a particularly grim prognosis. There is a need for a more fundamental understanding of the underlying mechanisms behind the therapeutic failure seen in GB patients. Previous research has indicated that GB’s RNA-interactome is linked to treatment response, but a large-scale, RNA-biotype-independent comprehensive investigation is currently lacking. We aim to provide such an investigation using GB patient-derived cell lines, representing the heterogeneous patient population. Utilizing novel methodologies to isolate RNA-protein complexes, combined with a multi-omics approach, will allow for the dissection of the composition and properties of these networks, ultimately aiding our understanding of the regulatory mechanisms behind GB treatment resistance.