Dataset Information

Proteomics, post-translational modifications, and integrative analyses reveal heterogeneity of molecular mechanisms within medulloblastoma subgroups

ABSTRACT: Archer TC, Ehrenberger T, Mundt F, Gold MP, Krug K, Mah CK, Mahoney EL, Daniel CJ, LeNail A, Ramamoorthy D, Mertins P, Mani DR, Zhang H, Gillette MA, Clauser K, Noble M, Tang LC, Francois JP, Silterra J, Jensen J, Tamayo P, Korshunov A, Pfister SM, Kool M, Northcott PA, Sears RC, Lipton JO, Carr SA, Mesirov JP, Pomeroy SL, Fraenkel E. Cancer Cell 2018. There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in Group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven tumors to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for new therapeutic strategies.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000082644 | MassIVE | Fri Jul 20 11:06:00 BST 2018

REPOSITORIES: MassIVE

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Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups.

Archer Tenley C TC Ehrenberger Tobias T Mundt Filip F Gold Maxwell P MP Krug Karsten K Mah Clarence K CK Mahoney Elizabeth L EL Daniel Colin J CJ LeNail Alexander A Ramamoorthy Divya D Mertins Philipp P Mani D R DR Zhang Hailei H Gillette Michael A MA Clauser Karl K Noble Michael M Tang Lauren C LC Pierre-François Jessica J Silterra Jacob J Jensen James J Tamayo Pablo P Korshunov Andrey A Pfister Stefan M SM Kool Marcel M Northcott Paul A PA Sears Rosalie C RC Lipton Jonathan O JO Carr Steven A SA Mesirov Jill P JP Pomeroy Scott L SL Fraenkel Ernest E

Cancer cell 20180901 3

There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and ...[more]

PMID: 30205044

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Project description:Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with group 3 (G3) MB representing the most aggressive subgroup associated with a poor prognosis and a remarkable ability to resist upfront multimodal therapy. Despite a low mutational burden of disease and MYC amplification identified as a independent factor associated with poor survivorship, efforts to target the MYC has met with limited therapeutic success. Consequently alternative mediators associated with the aggressive phenotype of G3 MB continues as a common goal within the MB community. Here we show how the neural stem cell determinant Musashi 1 (MSI1) is a central and vital moderator of G3 MB in both a MYC amplified mouse model of G3 MB and patient derived xenografts (PDX). Specifically, we modified the MYC amplified and p53 mutated (MP) mouse model of G3 MB to generate Msi1 conditional knockout mice (Msi1flox/flox), which led to the observation that MSI1 is required for tumor initiation of MP tumors. To identify the translational potential of these findings, we employed shRNA against Msi1 in multiple PDX lines, observing a striking deficit in multiple key stem cell features including self-renewal, proliferation, and failure to progress through the cell cycle. Notably, Msi1 inhibition resulted in a failure of tumor initiation, translating to a significantly prolonged survival, reaffirming the essential role for MSI1 in G3 MB. To determine how MSI1 symphonizes the anarchic post-transcriptional landscape of G3MB, we differentially analyzed the MSI1 binding sites in normal neural stem cells and G3 MB and subsequently compared the MSI1-binding transcriptome, and proteome following Msi1 inhibition. Comparative analysis suggested an integral role for post-transcriptional regulators, such as MSI1 and its binding prey mRNA, as a therapeutic target. Here we propose the neural RNA binding protein MSI1, as a master regulator, hijacked from its normal neural developmental function, orchestrating the aberrant translational landscape of G3 MB.