Exploring the Role of SPY1 and Musashi-1 in Glioblastoma Stem Cell Maintenance and Therapy Resistance

Glioblastoma (GBM) is the most aggressive type of brain, and due to its highly infiltrative and heterogeneous nature, GBM poses significant challenges to standard therapies. Glioblastoma is categorized by three genomic subtypes: Proneural, Classical and Mesenchymal, and contains therapy-resistant Glioma Stem Cells (GSCs), contributing to tumor heterogeneity. Cancer cells (including GBM) are characterized by uncontrolled cell proliferation, which is linked to cell cycle dysregulation. The cell cycle, regulated by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, ensures orderly progression in a normal cell. Spy1 (SPDYA/RingoA) is an atypical cell cycle regulator that controls cell proliferation and survival through unique activation of CDKs and promoting the G1/S phase transition. In GBM, elevated levels of Spy1 regulate CDK2 activity and drive clonal expansion of CD133+ GSCs. Spy1-CDK2 can also activate RNA-binding protein, Musashi-1 (Msi1), which plays a critical role in GSC maintenance through post-transcriptional regulation of NUMB and Notch pathway. Musashi-1 supports GSC populations to drive tumor initiation and resistance to differentiation. This study aims to understand the role of Msi1 in maintaining GSC properties and its potential correlation with specific subgroups, and how Msi1 influences GSC self-renewal, proliferation, and response to therapies, with the goal of identifying novel therapeutic strategies to overcome treatment resistance in GBM. The objective is to study the expression of Msi1 in different genetic subtypes of GBM as well as in selected GSC populations and to establish whether Spy1 mediated effects in GBM depend on Msi1 molecular function.