Thyroid Hormone Inhibits Medulloblastoma Growth by Inducing Tumor Cell Differentiation

Project Summary/Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite conventional treatment including surgery, chemotherapy and radiation, a significant proportion of MB patients still succumbs to this disease. Moreover, almost all patients suffer long-term side effects of the aggressive treatment, such as hearing loss and cognitive deficit. Improved strategies to treat MB are urgently needed. Thyroid hormone (TH) plays an important role in normal brain development, but the possible function of TH in MB pathogenesis is still unknown. Our recent studies revealed an unanticipated link between TH signaling and MB pathogenesis, with exciting therapeutic implications for MB treatment. In our preliminary studies, we found that TH induces the expression of NeuroD1, a helix-loop-helix transcription factor in MB cells and stimulates the terminal differentiation of tumor cells. Upon their differentiation, MB cells lose their tumorigenic potential and secrete glutamate interfering with the survival of surrounding MB cells. TH-induced differentiation inhibits MB cell proliferation, and represses MB growth in vivo. Based on these observations, we hypothesize that TH suppresses MB pathogenesis through inducing tumor cell differentiation. This hypothesis will be tested in three specific aims: 1) examine how TH promotes MB cell differentiation; 2) examine how tumor cell differentiation represses MB pathogenicity; 3) test if TH signaling can be exploited for MB therapy. Our studies will elucidate the mechanisms underlying terminal differentiation of MB cells, and establish an unprecedented association between TH and MB progression, which will pave the way for TH as a new therapeutic modality for MB.