The interplay of ascorbic acid and collagen deposition in the extracellular matrix of paediatric medulloblastoma
Publication Date
July 27, 2026
Creator
Dholakia, Menil
Abstract
Medulloblastoma is the most common malignant paediatric brain tumour, accounting for roughly 20% of all paediatric cancers of the central nervous system (CNS). Medulloblastoma can be divided into four molecular subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. SHH medulloblastoma is prevalent in infants (0-3 years) and adults. Current multimodal treatments, such as maximal surgical resection, craniospinal irradiation, and chemotherapy, have improved patient survival; however, they are still associated with significant long-term neurocognitive side effects in infants and the current treatment regimen does not eliminate the chances of tumour relapse, leading to poorer outcomes and quality of life for patients. Recent research indicates that extracellular matrix (ECM) composition and deposition modulate tumour behaviour and therapy response in SHH medulloblastoma. Ascorbic acid (AA), also known as vitamin C is an important cofactor in collagen production and has concentration dependant dual functionality as an antioxidant or pro-oxidant that may affect tumour microenvironmental dynamics and chemotherapy response. This study endeavours to link AA, collagen deposition, and chemotherapy response in SHH medulloblastoma models. DAOY (TP53 mutant) and ONS-76 (TP53 wild-type) cell lines were used to create 3D spheroid models that closely replicated SHH tumour architecture. Spheroids were treated with AA at physiological (100µM) and supraphysiological (2.5mM) concentrations, both alone and in conjunction with the chemotherapeutic drug cisplatin. Immunofluorescence imaging revealed that high-dose AA (2.5mM) increased extracellular collagen deposition and ECM density, but lower doses (100µM) produced minimal structural alterations. Functional experiments combining AA and cisplatin treatment revealed that physiological AA concentrations had a cytoprotective impact, lowering cisplatininduced cytotoxicity, whereas supraphysiological dosages dramatically increased spheroid disintegration, decreasing spheroid viability. Molecular investigations indicated that the transporters of AA and its oxidised form dehydroascorbic acid (DHA) namely, SLC23A2 (SVCT2) and SLC2A10 (GLUT10), have a modest differential expression between the two SHH cell lines. Inhibition of SVCT2 and GLUT transporters with sulfinpyrazone and cytochalasin B, respectively, reduced AA uptake and modified redox homeostasis. The findings from this study suggest that supraphysiological concentrations of AA functions as a pro-oxidant, increasing cytotoxic impact of chemotherapy, whereas physiological levels retain antioxidant and protective properties, and thus work in favour of the tumour. These findings open a promising avenue for improvement in medulloblastoma therapy, in turn improving patient outcomes. Overall, this study demonstrates that pharmacological AA could be an effective adjuvant in SHH medulloblastoma treatment, given that concentration, transporter expression, and tumour subtype are carefully assessed throughout clinical translation.
Item Type
ethesis
Thesis Type
MRes
Subjects (LC)
Associated Schools / Departments
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