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

Tenley C. Archer, Tobias Ehrenberger, Filip Mundt, Maxwell P. Gold, Karsten Krug, Clarence K. Mah, Elizabeth L. Mahoney, Colin J. Daniel, Alexander LeNail, Divya Ramamoorthy, Philipp Mertins, D. R. Mani, Hailei Zhang, Michael A. Gillette, Karl Clauser, Michael Noble, Lauren C. Tang, Jessica Pierre-François, Jacob Silterra, James JensenPablo Tamayo, Andrey Korshunov, Stefan M. Pfister, Marcel Kool, Paul A. Northcott, Rosalie C. Sears, Jonathan O. Lipton, Steven A. Carr, Jill P. Mesirov, Scott L. Pomeroy, Ernest Fraenkel

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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 cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.

Original languageEnglish (US)
Pages (from-to)396-410.e8
JournalCancer Cell
Volume34
Issue number3
DOIs
StatePublished - Sep 10 2018

Keywords

  • MYC
  • NU-7441
  • SHH
  • mass spectrometry
  • medulloblastoma
  • multi-omics
  • network integration
  • phospho-proteomics
  • proteo-genomics
  • radio sensitization

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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