ID #450 Metabolic determinants of radiation response across molecular subgroups of medulloblastoma
Rohit Mallick, Nina Struve, Verena Jendrossek, Johann MatschkeAbstract
Introduction
Medulloblastoma (MB) is the most common malignant pediatric brain tumor and comprises molecularly distinct subgroups with pronounced differences in prognosis and therapy response. While radiotherapy remains a cornerstone of treatment, intrinsic radioresistance in high-risk subtypes such as MYC-amplified Group 3 and TP53-mutated SHH-MB significantly limits therapeutic success and contributes to long-term toxicity. Increasing evidence suggests that metabolic plasticity critically influences the radiation response, yet subtype-specific metabolic adaptations remain insufficiently characterized.
Methods
Representative medulloblastoma cell models of SHH and Group 3/4 subtypes were subjected to radiobiological and functional metabolic characterization following irradiation. Short- and long-term cellular responses were assessed alongside radiation-induced alterations in mitochondrial function and cellular energy metabolism. Translational validation in preclinical models, including the chicken chorioallantoic membrane (CAM) model, is planned as a next step.
Results
Initial analyses revealed pronounced subtype-specific differences in radiation response, with SHH-MB models exhibiting enhanced proliferative capacity and metabolic adaptability compared to Group 3/4 models. Radiation exposure induced distinct metabolic responses, suggesting differential reliance on mitochondrial function and energy production pathways across MB subtypes. Collectively, these data support a model in which mitochondrial adaptability and energy metabolism are associated with subgroup-specific radiation response phenotypes.
Conclusion
Our data highlight fundamental differences in radiation-associated metabolic adaptations between medulloblastoma subgroups. Defining subgroup-specific metabolic dependencies and their coupling to irradiation-induced stress responses may support the rational development of combination strategies to improve therapeutic efficacy while potentially reducing treatment-associated toxicity. Ongoing studies aim to further delineate actionable metabolic vulnerabilities in high-risk medulloblastoma.
Acknowledgement
Supported by the German Federal Ministry of Research, Technology and Space (BMFTR), grant 02NUK090B and 02NUK090A.