Journal article
ATOH1 promotes leptomeningeal dissemination and metastasis of Sonic Hedgehog subgroup medulloblastomas
Cancer research (Chicago, Ill.), Vol.77(14), pp.3766-3777
07/15/2017
DOI: 10.1158/0008-5472.CAN-16-1836
PMCID: PMC5512702
PMID: 28490517
Abstract
Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive MB 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 MB, animals with
Atoh1
transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely,
ATOH1
expression was detected consistently in recurrent and metastatic SHH MB. ChIP-seq 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 (BMP) or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying MB metastasis that offers possible therapeutic opportunities.
Details
- Title: Subtitle
- ATOH1 promotes leptomeningeal dissemination and metastasis of Sonic Hedgehog subgroup medulloblastomas
- Creators
- Katie B GrausamSamuel D. R DooyemaLaure BihannicHasitha PremathilakeA. Sorana MorrissyAntoine ForgetAmanda M SchaeferJustin H GundelachSlobodan MacuraDiane M MaherKevin WangAlex H HeglinXijin GeErliang ZengStephanie PugetIndra ChandrasekarKameswaran SurendranRichard J BramUlrich SchüllerMichael D TalyorOlivier AyraultHaotian Zhao
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.77(14), pp.3766-3777
- DOI
- 10.1158/0008-5472.CAN-16-1836
- PMID
- 28490517
- PMCID
- PMC5512702
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 07/15/2017
- Academic Unit
- Preventive and Community Dentistry; Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute; Biostatistics; Dental Research
- Record Identifier
- 9984065471202771
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