Epigenetic regulation in SHH-subgroup medulloblastoma formation

• Applicant: Daisuke Kawauchi, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320995250

Medulloblastoma is one of the most common malignant pediatric brain tumors arising in the cerebellum. Recent tremendous efforts on molecular characterization of medulloblastoma have classified this disease into at least four subgroups: WNT, Sonic hedgehog (SHH), Group3 and Group4. Among these subgroups, the etiology of SHH-subgroup medulloblastoma (MBSHH) that comprise approximately 30% of all human medulloblastoma has been most clearly established. MBSHH are derived from cerebellar granule neuron precursors (GNPs) based on abnormal activation of the SHH signaling pathway. The blockade of the SHH signaling with Smoothened (Smo) inhibitors Cyclopamine and GDC-0449 led to tumor regression, suggesting involvement of SHH signaling in tumor initiation and progression. Although Smo inhibitors are attractive candidate drugs, potent side effects and resistance induction have been reported. Especially, gain of function mutations and amplification/overexpression of effector genes downstream of Smo result in primary resistance of tumors against these drugs. Therefore, other approaches to repress SHH signaling and/or its downstream targets remain to be desperately needed. Chromatin modifiers are one potential approach for SHH signaling repression. Considering the fact that chromatin states are reversible, the understanding of how such chromatin modifiers regulate proliferation of GNPs would help to establish new therapeutic methods using epigenetic drugs. Indeed, recent deep sequencing analyses using human primary MBs have identified specific recurrent loss-of-function mutations of chromatin modifiers in MBSHH. Nevertheless, the role of these genes in granule cell differentiation and MB formation has not been investigated to date. In this project, we will focus on the role of these chromatin modifiers in health and disease, and explore their function as a tumor suppressor gene using animal models. As the first step of the project, we will focus on Bcor (BCL6 transcriptional corepressor) that we have recently identified as a novel tumor suppressor gene in a genetic mouse model of MBSHH. While we found that Bcor loss accelerates MBSHH formation in a tumor-prone Ptch1 heterozygous background, the mechanistic contribution of Bcor deletion to tumorigenesis of MBSHH remains to be studied. Thus, the main aim of this project is to explore the molecular mechanisms underlying acceleration of MBSHH development in a Bcor-deficient background. Of note, the Bcor gene has been identified as a recurrently mutated in many other cancers thus we hypothesize that our proposed project would provide important insights into general mechanisms underlying development of not only MBSHH but also other Bcor-related cancers.

• DFG Programme: Research Grants