Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
Open accessPublished version of a preprint
Abstract
Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC -overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.
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Cites
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Self-citationIntertumoral Heterogeneity within Medulloblastoma Subgroups
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- Authors
- Kameda-Smith, M. M., Zhu, H., Luo, E.-C., Suk, Y., Xella, A., Yee, B., Chokshi, C., Xing, S., Tan, F., Fox, R. G., Adile, A. A., Bakhshinyan, D., Brown, K., Gwynne, W. D., Subapanditha, M., Miletic, P., Picard, D., Burns, I., Moffat, J., Paruch, K., Fleming, A., Hope, K., Provias, J. P., Remke, M., Lu, Y., Reya, T., Venugopal, C., Reimand, J., Wechsler-Reya, R. J., Yeo, G. W., & Singh, S. K.
- Affiliations
- McMaster University (CA)
- Ontario Institute for Cancer Research (CA)
- University of California San Diego (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of Toronto (CA)
- Düsseldorf University Hospital (DE)
- Masaryk University (CZ)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Yeo, Gene W.
- Singh, Sheila K.
- ORCID
- Kameda-Smith, Michelle M.
- Zhu, Helen
- Luo, En-Ching
- Suk, Yujin
- Xella, Agata
- Yee, Brian
- Chokshi, Chirayu
- Tan, Frederick
- Fox, Raymond G.
- Adile, Ashley A.
- Bakhshinyan, David
- Brown, Kevin
- Gwynne, William D.
- Miletic, Petar
- Picard, Daniel
- Burns, Ian
- Moffat, Jason
- Paruch, Kamil
- Fleming, Adam
- Hope, Kristin
- Remke, Marc
- Reya, Tannishtha
- Venugopal, Chitra
- Reimand, Jüri
- Wechsler-Reya, Robert J.
- Yeo, Gene W.
- Singh, Sheila K.
- Venue
- Nature Communications
- Published
- 2022-12-06
- Volume
- 13
- Issue
- 1
- Pages
- 7506-7506
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9726987
- OpenAlex
- W4311583012
- Cited by
- 7
- References
- 8
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 4
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-01-10)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- California Institute for Regenerative Medicine
- Alex's Lemonade Stand Foundation for Childhood Cancer (CA159859)
- Neurosurgery Research and Education Foundation
- McMaster University
- Ontario Institute for Cancer Research
- Government of Ontario
- University of California, San Diego
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- National Heart, Lung, and Blood Institute (T32HL086344)
- National Cancer Institute (CA009523, CA30199, CA159859, T32CA009523, P30CA030199, R01CA159859, R35CA197699, P30CA30199)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- pediatric medulloblastoma, Group 3 medulloblastoma, MYC amplification, Musashi-1, RNA-binding proteins, protein-protein interaction network, post-transcriptional regulation, cancer stem cells, patient-derived xenografts, multi-omics integration, therapeutic target
- MeSH terms
- Animals, Brain Neoplasms, Cerebellar Neoplasms, Humans, Medulloblastoma, Nerve Tissue Proteins, RNA-Binding Proteins, Proteomics, Mice
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