Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Walderik W Zomerman, Sabine L A Plasschaert, Siobhan Conroy, Frank J Scherpen, Tiny G J Meeuwsen-de Boer, Harm J Lourens, Sergi Guerrero Llobet, Marlinde J Smit, Lorian Slagter-Menkema, Annika Seitz, Corrie E M Gidding, Esther Hulleman, Pieter Wesseling, Lisethe Meijer, Leon C van Kempen, Anke van den Berg, Daniël O Warmerdam, Frank A E Kruyt, Floris Foijer, Marcel A T M van VugtWilfred F A den Dunnen, Eelco W Hoving, Victor Guryev, Eveline S J M de Bont, Sophia W M Bruggeman

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Abstract

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

Original languageEnglish
Pages (from-to)3206-3216
Number of pages11
JournalCell reports
Volume22
Issue number12
DOIs
Publication statusPublished - 20-Mar-2018

Keywords

  • CURRENT CONSENSUS
  • CANCER GENOME
  • MYC
  • STEM
  • CHILDHOOD
  • SUBGROUPS
  • REVEALS
  • P53
  • INHIBITION
  • MECHANISM

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