Date of Award

5-25-2024

Publication Type

Thesis

Degree Name

M.Sc.

Department

Biological Sciences

Keywords

Cell Cycle;Medulloblastoma;Spy1;Stemness;Tumour Initiating Cells;Zebrafish

Supervisor

Lisa Porter

Abstract

Medulloblastoma (MB) is one of the most common malignant brain tumours that has a higher incidence of occurrence in children. Sonic Hedgehog (SHH) MB, named after the Sonic Hedgehog pathway, accounts for approximately 30% of all MB cases. Group 3 is one of the most aggressive and poorly identified of MB subgroups due to its various genetic alterations. Activation of the SHH signaling cascade is important for tissue development and is important in the maintenance of somatic stem cells including neural tissues. However, the SHH MB subgroup are comprised of different genetic mutations that are identified along the signaling cascade, causing its constant activation which can lead to tumour progression. Some of the SHH target genes are developmental regulators, including the Cyclin E1 (CCNE1) gene, and in stem cells, it promotes other gene expressions such as CD133. The SHH MB tumours are heterogeneous in nature and contain a small subset of brain tumour initiating cells (TICs) that self-renew and drive uncontrolled tumour growth. TICs can be identified by their cell surface marker, CD133, and have been known to drive proliferation and maintenance of the heterogeneous tumour. Thus, BTICs may account for tumour resistance to current conventional therapy regimens. The cell cycle plays a crucial role in driving the TIC expansion through uncontrolled progression of the cell cycle checkpoints as well as inhibiting the natural cyclin-dependent kinase inhibitors (CKIs) activity. Chemotherapy efficacy in treatment can be insignificant to a subset of patients and may lead to high toxicity when undergoing treatment. A cyclin-like protein, Spy1, can directly bind to and activate CDKs. Spy1 promotes the cell cycle progression through overriding cell cycle checkpoints and inhibiting/lowering sensitivity to the natural CKIs. Previous studies showed that Spy1 is capable of expanding BTIC populations in multiple types of neural cancers including Glioblastoma (GBM), and Neuroblastoma (NB). Therefore, targeting the cyclin-like protein may be a potential target in Medulloblastoma and subsequently may increase the efficacy of current therapy regimens.

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