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 Vugt; Wilfred F.A. den Dunnen; Eelco W. Hoving; Victor Guryev; Eveline S.J.M. de Bont; Sophia W.M. Bruggeman

Cell Reports (Mar 2018)

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 Vugt,
Wilfred F.A. den Dunnen,
Eelco W. Hoving,
Victor Guryev,
Eveline S.J.M. de Bont,
Sophia W.M. Bruggeman

Affiliations

Walderik W. Zomerman: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Sabine L.A. Plasschaert: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA Utrecht, the Netherlands
Siobhan Conroy: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Frank J. Scherpen: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Tiny G.J. Meeuwsen-de Boer: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Harm J. Lourens: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Sergi Guerrero Llobet: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Marlinde J. Smit: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Lorian Slagter-Menkema: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Annika Seitz: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Corrie E.M. Gidding: Department of Pediatric Oncology/Pediatrics, Radboud University Medical Center Nijmegen, Geert Groteplein Zuid 10, 6525 HB Nijmegen, the Netherlands
Esther Hulleman: Department of Pediatric Oncology/Hematology, Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Pieter Wesseling: Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Department of Pathology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Lisethe Meijer: Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Leon C. van Kempen: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Department of Pathology, McGill University, 3775 University Street, Montreal, QC H3A 2B4, Canada
Anke van den Berg: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Daniël O. Warmerdam: iPSC CRISPR Center, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Frank A.E. Kruyt: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Floris Foijer: iPSC CRISPR Center, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; ERIBA, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Marcel A.T.M. van Vugt: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Wilfred F.A. den Dunnen: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Eelco W. Hoving: Department of Neurosurgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA Utrecht, the Netherlands
Victor Guryev: ERIBA, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Eveline S.J.M. de Bont: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands
Sophia W.M. Bruggeman: Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; Corresponding author

Journal volume & issue: Vol. 22, no. 12
pp. 3206 – 3216

Abstract

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Summary: 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. : Using peptide phosphorylation profiling, Zomerman et al. identify two medulloblastoma phosphoprotein-signaling profiles that have prognostic value and are potentially targetable. They find that these profiles extend across transcriptome-based subgroup borders. This suggests that diverse genetic information converges on common protein-signaling pathways and highlights protein-signaling as a unique information layer. Keywords: medulloblastoma, protein-signaling, protein synthesis, MYC, TP53, proteome, phosphoproteome

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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