Abstract 1595: Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma

Abstract

Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity by regulating terminal differentiation of tumor cells. Elimination or reduction in the levels of TH frees the unliganded TH receptor, TRα, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives terminal differentiation of neuronal progenitors as well as MB cells. However, increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and reducing MB growth. Moreover, TH promotes extensive differentiation and reduced proliferation of tumor cells from multiple molecular subtypes of MB including the hedgehog (HH) group as well as group 3 (G3) MB, indicating that TH-induced differentiation is not restricted by the oncogenic driver mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB by promoting tumor cell differentiation, with no obvious increase in tumor cell death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, and they establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality targeting tumor cell differentiation. Citation Format: Zeng-Jie Yang, Yijun Yang Yang, Allie Heller. Thyroid hormone drives the terminal differentiation of tumor cells in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1595.