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
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
