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, Sheila K Singh

Nature communications · 2022 · Vol. 13 (1) · pp. 7506

PubMed DOI PMC Full Text

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.

Publication Types

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]

Keywords

[]

MeSH Terms

["Animals", "Mice", "Humans", "Proteomics", "Medulloblastoma", "RNA-Binding Proteins", "Brain Neoplasms", "Cerebellar Neoplasms", "Nerve Tissue Proteins"]

Funding

R01 CA159859 NCI NIH HHS (United States)

T32 HL086344 NHLBI NIH HHS (United States)

P30 CA030199 NCI NIH HHS (United States)

T32 CA009523 NCI NIH HHS (United States)

R35 CA197699 NCI NIH HHS (United States)

Linked Datasets (3)

GSE126337 GSE via ncbi_elink

GEO

Musashi-1 is a master regulator of aberrant translation in Group 3 medulloblastoma

Homo sapiens

12 data files

File	Type	Size
MB002-03-5-1_S16_R1_001.fastq.gz	RNA-Seq	541.2 MB
MB002-03-5-1_S16_R1_001.fastq.gz	RNA-Seq	541.2 MB
MB002-03-5-2_S17_R1_001.fastq.gz	RNA-Seq	459.5 MB
MB002-03-5-2_S17_R1_001.fastq.gz	RNA-Seq	459.5 MB
MB002-03-5-3_S18_R1_001.fastq.gz	RNA-Seq	285.9 MB
MB002-03-5-3_S18_R1_001.fastq.gz	RNA-Seq	285.9 MB
MB002-shGFP-1_S19_R1_001.fastq.gz	RNA-Seq	384.7 MB
MB002-shGFP-1_S19_R1_001.fastq.gz	RNA-Seq	384.7 MB
MB002-shGFP-2_S20_R1_001.fastq.gz	RNA-Seq	342.5 MB
MB002-shGFP-2_S20_R1_001.fastq.gz	RNA-Seq	342.5 MB
MB002-shGFP-3_S21_R1_001.fastq.gz	RNA-Seq	321.3 MB
MB002-shGFP-3_S21_R1_001.fastq.gz	RNA-Seq	321.3 MB

GSE134597 GSE via ncbi_elink

GEO

Musashi1 is a master regulator of aberrant translation in Group 3 medulloblastoma

Homo sapiens

16 data files

File	Type	Size
GFP2_poly_S32_L003_R1_001.fastq.gz	RNA-Seq	888.9 MB
GFP2_poly_S32_L003_R1_001.fastq.gz	RNA-Seq	888.9 MB
GFP2_S26_L003_R1_001.fastq.gz	RNA-Seq	765.2 MB
GFP2_S26_L003_R1_001.fastq.gz	RNA-Seq	765.2 MB
GFP3_poly_S33_L003_R1_001.fastq.gz	RNA-Seq	724.4 MB
GFP3_poly_S33_L003_R1_001.fastq.gz	RNA-Seq	724.4 MB
GFP3_S27_L003_R1_001.fastq.gz	RNA-Seq	717.2 MB
GFP3_S27_L003_R1_001.fastq.gz	RNA-Seq	717.2 MB
MSI2_poly_S35_L003_R1_001.fastq.gz	RNA-Seq	778.8 MB
MSI2_poly_S35_L003_R1_001.fastq.gz	RNA-Seq	778.8 MB
MSI2_S29_L003_R1_001.fastq.gz	RNA-Seq	778.8 MB
MSI2_S29_L003_R1_001.fastq.gz	RNA-Seq	778.8 MB
MSI3_poly_S36_L003_R1_001.fastq.gz	RNA-Seq	783.3 MB
MSI3_poly_S36_L003_R1_001.fastq.gz	RNA-Seq	783.3 MB
MSI3_S30_L003_R1_001.fastq.gz	RNA-Seq	868.2 MB
MSI3_S30_L003_R1_001.fastq.gz	RNA-Seq	868.2 MB

GSE126263 GSE via ncbi_elink

GEO

Musashi-1 is a master regulator of aberrant translation in Group 3 medulloblastoma

Homo sapiens

12 data files

File	Type	Size
SRR8548827	RIP-Seq	707.5 MB
SRR8548827	RIP-Seq	707.5 MB
SRR8548828	RIP-Seq	632.8 MB
SRR8548828	RIP-Seq	632.8 MB
SRR8548829	RIP-Seq	508.2 MB
SRR8548829	RIP-Seq	508.2 MB
SRR8548830	RIP-Seq	1.5 GB
SRR8548830	RIP-Seq	1.5 GB
SRR8548831	RIP-Seq	1.4 GB
SRR8548831	RIP-Seq	1.4 GB
SRR8548832	RIP-Seq	829.1 MB
SRR8548832	RIP-Seq	829.1 MB

Potentially Related Datasets (4)

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

PXD012432 PXD PRIDE

GSE126337 GSE GEO

GEO

Musashi-1 is a master regulator of aberrant translation in Group 3 medulloblastoma

GSE126263 GSE GEO

GEO

Musashi-1 is a master regulator of aberrant translation in Group 3 medulloblastoma

GSE134597 GSE GEO

GEO

Musashi1 is a master regulator of aberrant translation in Group 3 medulloblastoma

Analysis Pipelines (3)

GSE126263 eCLIP Data Processing 25 steps

eCLIP geo_data_processing GSE126263

GSE126337 Data Processing 3 steps

geo_data_processing GSE126337

GSE134597 Data Processing 4 steps

geo_data_processing GSE134597