Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma

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Authors

KAMEDA-SMITH Michelle M. M. ZHU Helen LUO En-Ching SUK Yujin XELLA Agata YEE Brian CHOKSHI Chirayu XING Sansi TAN Frederick FOX Raymond G. G. ADILE Ashley A. A. BAKHSHINYAN David BROWN Kevin GWYNNE William D. D. SUBAPANDITHA Minomi MILETIC Petar PICARD Daniel BURNS Ian MOFFAT Jason PARUCH Kamil FLEMING Adam HOPE Kristin PROVIAS John P P REMKE Marc LU Yu REYA Tannishtha VENUGOPAL Chitra REIMAND Juri WECHSLER-REYA Robert J J YEO Gene W W SINGH Sheila K K

Year of publication 2022
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Faculty of Science

Citation
Web https://doi.org/10.1038/s41467-022-35118-3
Doi http://dx.doi.org/10.1038/s41467-022-35118-3
Keywords Cancer stem cells; Neural stem cells; Paediatric cancer
Description 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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