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

Michelle M. Kameda-Smith, Helen Zhu, En-Ching Luo, Yujin Suk, Agata Xella, Brian Yee, Chirayu Chokshi, Sansi Xing, Frederick Tan, Raymond G. Fox, Ashley A. Adile, David Bakhshinyan, Kevin Brown, William D. Gwynne, Minomi Subapanditha, Petar Miletic, Daniel Picard, Ian Burns, Jason Moffat, Kamil Paruch, Adam Fleming, Kristin Hope, John P. Provias, Marc Remke, Yu Lu, Tannishtha Reya, Chitra Venugopal, Jüri Reimand, Robert J. Wechsler-Reya (), Gene W. Yeo () and Sheila K. Singh ()
Additional contact information
Michelle M. Kameda-Smith: McMaster University
Helen Zhu: Computational Biology Program, Ontario Institute for Cancer Research
En-Ching Luo: University of California at San Diego
Yujin Suk: McMaster University
Agata Xella: Sanford Burnham Prebys Medical Discovery Institute
Brian Yee: University of California at San Diego
Chirayu Chokshi: McMaster University
Sansi Xing: McMaster University
Frederick Tan: University of California at San Diego
Raymond G. Fox: University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine
Ashley A. Adile: McMaster University
David Bakhshinyan: McMaster University
Kevin Brown: University of Toronto
William D. Gwynne: McMaster University
Minomi Subapanditha: McMaster University
Petar Miletic: McMaster University
Daniel Picard: University Hospital Düsseldorf
Ian Burns: McMaster University
Jason Moffat: University of Toronto
Kamil Paruch: Masaryk University
Adam Fleming: McMaster University, Departments of Pediatrics, Hematology and Oncology Division
Kristin Hope: McMaster University
John P. Provias: McMaster University, Departments of Neuropathology
Marc Remke: University Hospital Düsseldorf
Yu Lu: McMaster University
Tannishtha Reya: University of California San Diego School of Medicine, Sanford Consortium for Regenerative Medicine
Chitra Venugopal: McMaster University
Jüri Reimand: Computational Biology Program, Ontario Institute for Cancer Research
Robert J. Wechsler-Reya: Sanford Burnham Prebys Medical Discovery Institute
Gene W. Yeo: University of California at San Diego
Sheila K. Singh: McMaster University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35118-3

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DOI: 10.1038/s41467-022-35118-3

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