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

doi:10.1016/j.celrep.2018.02.089

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

Cell Rep. 2018 Mar 20;22(12):3206-3216. doi: 10.1016/j.celrep.2018.02.089.

Authors

Walderik W Zomerman¹, Sabine L A Plasschaert², Siobhan Conroy³, Frank J Scherpen¹, Tiny G J Meeuwsen-de Boer¹, Harm J Lourens¹, Sergi Guerrero Llobet⁴, Marlinde J Smit¹, Lorian Slagter-Menkema⁵, Annika Seitz³, Corrie E M Gidding⁶, Esther Hulleman⁷, Pieter Wesseling⁸, Lisethe Meijer⁹, Leon C van Kempen¹⁰, Anke van den Berg³, Daniël O Warmerdam¹¹, Frank A E Kruyt⁴, Floris Foijer¹², Marcel A T M van Vugt⁴, Wilfred F A den Dunnen³, Eelco W Hoving¹³, Victor Guryev¹⁴, Eveline S J M de Bont¹, Sophia W M Bruggeman¹⁵

Affiliations

¹ Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
² 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.
³ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
⁴ Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
⁵ 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.
⁶ Department of Pediatric Oncology/Pediatrics, Radboud University Medical Center Nijmegen, Geert Groteplein Zuid 10, 6525 HB Nijmegen, the Netherlands.
⁷ 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.
⁸ 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.
⁹ Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
¹⁰ 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.
¹¹ iPSC CRISPR Center, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
¹² 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.
¹³ 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.
¹⁴ ERIBA, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands.
¹⁵ Departments of Pediatric Oncology and Hematology/Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. Electronic address: [email protected].

PMID: 29562177
DOI: 10.1016/j.celrep.2018.02.089

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.

Keywords: MYC; TP53; medulloblastoma; phosphoproteome; protein synthesis; protein-signaling; proteome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / metabolism*
Cerebellar Neoplasms / pathology
Gene Expression Profiling
Hedgehog Proteins / metabolism*
Humans
Medulloblastoma / genetics
Medulloblastoma / metabolism*
Medulloblastoma / pathology
Phosphorylation
Proto-Oncogene Proteins c-myc / biosynthesis
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
RNA, Messenger / metabolism
Signal Transduction
Tumor Suppressor Protein p53 / genetics

Substances

Hedgehog Proteins
MYC protein, human
Proto-Oncogene Proteins c-myc
RNA, Messenger
TP53 protein, human
Tumor Suppressor Protein p53