Jones, Manon
(2025)
Investigating the role of ascorbic acid and its transporters in medulloblastoma.
MRes thesis, University of Nottingham.
Abstract
Medulloblastoma is a highly malignant paediatric brain tumour, accounting for 20% of cases. Current treatment achieves a 70% 5-year-survival rate but can result in long-term neurological side effects. Treatment is further complicated by the disease’s heterogeneity, comprising four molecular subgroups: Group 3, Group 4, SHH and WNT. Novel therapeutic strategies are urgently needed to improve outcomes while addressing both treatment toxicity and the diverse molecular landscape. Adjuvant therapies that enhance treatment efficacy could reduce therapeutic doses and minimise side effects. A unique feature of the SHH subgroup is a collagen-rich extracellular matrix (ECM) shell, which is associated with improved survival, possibly by limiting tumour growth and invasiveness. This makes it a potential target for therapeutic manipulation in SHH tumours. Ascorbic acid (Vitamin C) plays a critical role as a co-factor in collagen production and could influence the collagen-rich ECM shell encapsulating SHH tumours. In addition, at high doses, ascorbic acid generates reactive oxygen species (ROS) via the Fenton reaction, leading to enhanced oxidative stress. Therefore, high-dose ascorbic acid could be a compelling candidate as an adjuvant treatment of SHH tumours, by promoting a tumour-restrictive microenvironment and increasing oxidative stress to enhance current treatment efficacy.
This thesis investigated the expression of ascorbic acid transporter genes in medulloblastoma patients, with a focus on SHH tumours. Analysis identified GLUT10 and SVCT2 as potential players in medulloblastoma biology, with differential expression linked to survival outcomes in SHH patients. These transporters were also significantly correlated with genes involved in antioxidant activity and collagen metabolism, including those contributing to the ECM shell in SHH tumours. To explore the functional effects of ascorbic acid, SHH spheroids, a 3D cell culture model that mimics tumour architecture, were treated with increasing concentrations of ascorbic acid. Physiological concentrations promoted spheroid growth, while high-dose ascorbic acid, when combined with the chemotherapeutic agent cisplatin, reduced spheroid size, suggesting an enhancement of cisplatin’s anti-proliferative effects. To investigate the underlying mechanism, acute ROS production in spheroids was measured following treatment. Pre-treatment with physiological ascorbic acid protected SHH spheroids from cisplatin-induced oxidative stress, whereas high-dose ascorbic acid exacerbated ROS production in pre-stressed spheroids. These findings suggest that high-dose ascorbic acid could enhance ROS generation achieved by a chemotherapeutic alone. Future research should further explore the potential synergy between ascorbic acid and cisplatin, as well as determine whether ascorbic acid-mediated spheroid growth is due to increased collagen deposition. This would help establish high-dose ascorbic acid as a potential adjuvant therapy in SHH medulloblastoma.
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