ATOH1 promotes leptomeningeal dissemination and metastasis of sonic hedgehog subgroup medulloblastomas

Abstract

Medulloblastoma arising from the cerebellum is the most like tumor xenografts. Conversely, ATOH1 expression was common pediatric brain malignancy, with leptomeningeal metas-detected consistently in recurrent and metastatic SHH medullo-tases often present at diagnosis and recurrence associated with blastoma. Chromatin immunoprecipitation sequencing and gene poor clinical outcome. In this study, we used mouse medullo-expression profiling identified candidate ATOH1 targets in tumor blastoma models to explore the relationship of tumor pathophys-cells involved in development and tumorigenesis. Among these iology and dysregulated expression of the NOTCH pathway targets specific to metastatic tumors, there was an enrichment in transcription factor ATOH1, which is present in aggressive medul-those implicated in extracellular matrix remodeling activity, cyto-loblastoma subtypes driven by aberrant Sonic Hedgehog/Patched skeletal network and interaction with microenvironment, indicat-(SHH/PTCH) signaling. In experiments with conditional ATOH1 ing a shift in transcriptomic and epigenomic landscapes during mouse mutants crossed to Ptch1þ/ mice, which develop SHH-metastasis. Treatment with bone morphogenetic protein or SHH driven medulloblastoma, animals with Atoh1 transgene expres-pathway inhibitors decreased tumor cell proliferation and supsion developed highly penetrant medulloblastoma at a young age pressed metastatic tumor growth, respectively. Our work reveals a with extensive leptomeningeal disease and metastasis to the spinal dynamic ATOH1-driven molecular cascade underlying medullo-cord and brain, resembling xenografts of human SHH medulloblastoma metastasis that offers possible therapeutic opportunities.