MDB-15. Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children, highlighting the urgent need for improved treatment strategies. Our research has demonstrated that medulloblastoma tumor cells can undergo terminal differentiation. Following differentiation, these tumor cells lose both their proliferative and tumorigenic capacities, suggesting that inducing terminal differentiation could serve as a novel therapeutic approach for medulloblastoma. Recently, we identified a critical role for thyroid hormone (TH) in promoting tumor cell differentiation. Reduced TH levels allow its receptor, TRα1, to bind to EZH2, repressing the expression of NeuroD1, a transcription factor essential for tumor cell differentiation. Increasing TH levels disrupts the interaction between TRα1 and EZH2, reversing this repression and upregulating NeuroD1 expression. This process induces terminal differentiation of tumor cells and significantly reduces MB growth. Notably, our findings show that TH-induced differentiation is effective across multiple molecular subgroups of medulloblastoma, making it a potentially universal therapeutic option. These results establish an unprecedented link between thyroid hormone signaling and medulloblastoma pathogenesis. By targeting the differentiation capacity of tumor cells, TH therapy presents a novel and promising approach to suppress tumor growth while potentially minimizing the toxicity associated with conventional treatments.