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Cancer Cell. 2018 Sep 10;34(3):379-395.e7. doi: 10.1016/j.ccell.2018.08.002.

Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.

Author information

1
Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France. Electronic address: antoine.forget@curie.fr.
2
Institut Curie, 26 rue d'Ulm, 75005 Paris, France; PSL Research University, 75005 Paris, France; Inserm, U900, 75005 Paris, France; Mines Paris Tech, 77305 cedex Fontainebleau, France.
3
Department of Pediatric Neurosurgery, Necker University Hospital, University Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
4
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany.
5
Department of Pediatric Neuro-Oncogenomics, DKFZ, Heidelberg, Germany; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; DKTK, Partner Site, Essen/Düsseldorf, Germany.
6
Proteomics and Mass Spectrometry Laboratory, Institut Curie, PSL Research University, 75005 Paris, France.
7
Department of Neuropathology, Sainte-Anne Hospital, 75014 Paris, France; University Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
8
Department of Pediatric and Adolescent Oncology, Gustave Roussy, Rue Edouard Vaillant, 94805 Villejuif, France.
9
Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
10
Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France; Institut Curie, Centre de Recherche, Plateforme d'Histologie, Orsay 91405, France.
11
Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
12
Paris-Sciences-Lettres Research University, Institut Curie Research Center, SiRIC, Laboratory of Translational Research in Pediatric Oncology, Paris 75005, France; Paris-Sciences-Lettres Research University, Institut Curie Research Center, INSERM U830, Laboratory of Biology and Genetics of Cancers, Paris 75005, France.
13
Division of Haematology/Oncology, Hospital for Sick Children and Department of Paediatrics, Hospital for Sick Children, Toronto, ON, Canada.
14
Clinical Cooperation Unit Neuropathology (G380), German Cancer Research Center (DKFZ), and Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
15
Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
16
Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; Departments of Surgery, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
17
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
18
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: d.kawauchi@dkfz-heidelberg.de.
19
Institut Curie, 26 rue d'Ulm, 75005 Paris, France; PSL Research University, 75005 Paris, France; Inserm, U900, 75005 Paris, France; Mines Paris Tech, 77305 cedex Fontainebleau, France. Electronic address: emmanuel.barillot@curie.fr.
20
Department of Pediatric Neuro-Oncogenomics, DKFZ, Heidelberg, Germany; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; DKTK, Partner Site, Essen/Düsseldorf, Germany. Electronic address: marc.remke@med.uni-duesseldorf.de.
21
Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France. Electronic address: olivier.ayrault@curie.fr.

Abstract

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.

KEYWORDS:

medulloblastoma; multi-omics; proteomics

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