The Cyclin-Like Protein Spy1 Regulates Senescence in Glioblastoma (GBM)

Glioblastoma (GBM) is a highly aggressive malignant brain tumour with a poor prognosis despite intensive conventional therapies. A key challenge in treating GBM is its ability to resist treatment, with a subset of tumour cells surviving and entering cellular senescence, a state of irreversible cell cycle arrest. While senescence initially halts tumour growth, prolonged senescence can contribute to tumor recurrence. Spy1, a cyclin-like protein, is elevated in GBM and promotes cell cycle progression by activating cyclin-dependent kinases (CDKs) and overriding cell cycle checkpoints. We hypothesize that Spy1 promotes GBM tumour growth and progression by enabling cancerous cells to evade senescence. Using in vitro and ex-vivo systems, this project will explore Spy1’s influence on senescence in GBM and assesses whether Spy1 targeting can enhance the effect of therapies targeting senescent cells. Spy1 will first be knocked down in GBM cell lines, and the levels of senescence will be evaluated through senescence-associated β-galactosidase staining and transcriptional analysis of senescence markers. These assessments will be replicated in Spy1-knockdown GBM cell lines subjected to temozolomide, the conventional treatment for GBM. Furthermore, this project will explore the combination of Spy1 inhibition with senolytic drugs, which are designed to eliminate senescent cells. The therapeutic efficacy of this combination will be evaluated through cell viability assays to assess cell death. This research will contribute to the understanding of Spy1’s role in GBM and its potential as a novel therapeutic target, potentially paving the way for personalized therapies to prevent GBM progression.