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

• DOI: 10.1016/j.celrep.2018.02.089
• Publication Date: 2018-03-21T00:24:14Z
• Authors: Walderik W. Zomerman; Sabine L.A. Plass...; Siobhan Conroy; Frank J. Scherpen; Tiny G.J. Meeuwse...; Harm J. Lourens; Sergi Guerrero Ll...; Marlinde J. Smit; Lorian Slagter-Me...; 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...; Wilfred F.A. den ...; Eelco W. Hoving; Victor Guryev; Eveline S.J.M. de...; Sophia W.M. Brugg...
• Keywords: MECHANISM; 0301 basic medicine; QH301-705.5; CHILDHOOD; INHIBITION; CURRENT CONSENSUS; MYC; CANCER GENOME; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; REVEALS; SUBGROUPS; Humans; Hedgehog Proteins; Paediatrics - Radboud University Medical Center; RNA, Messenger; Biology (General); Phosphorylation; Cerebellar Neoplasms; P53; Gene Expression Profiling; STEM; Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences; 3. Good health; Tumor Suppressor Protein p53; Medulloblastoma; Signal Transduction

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.