ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

作者：Grausam Katie B; Dooyema Samuel D R; Bihannic Laure; Premathilake Hasitha; Morrissy A Sorana; Forget Antoine; Schaefer Amanda M; Gundelach Justin H; Macura Slobodan; Maher Diane M; Wang Xin; Heglin Alex H; Ge Xijin; Zeng Erliang; Puget Stephanie; Chandrasekar Indra; Surendran Kameswaran; Bram Richard J; Schueller Ulrich; Talyor Michael D; Ayrault Olivier; Zhao Haotian^*

来源：Cancer Research, 2017, 77(14): 3766-3777.

DOI：10.1158/0008-5472.CAN-16-1836

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metas-tases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1(-/-) mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medullo-blastomametastasis that offers possible therapeutic opportunities.

• 出版日期2017-7-15