Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

Cancer Cell. 2018 Sep 10;34(3):379-395.e7. doi: 10.1016/j.ccell.2018.08.002.

Abstract

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

Keywords: medulloblastoma; multi-omics; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / pathology*
  • Cerebellum / pathology
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Infant
  • Male
  • Medulloblastoma / genetics
  • Medulloblastoma / pathology*
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Proteome / metabolism
  • Proteomics / methods
  • Receptor, ErbB-4 / metabolism*
  • Signal Transduction
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*

Substances

  • Proteome
  • ERBB4 protein, human
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • src-Family Kinases