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

Antoine Forget; Loredana Martignetti; Stéphanie Puget; Laurence Calzone; Sebastian Brabetz; Daniel Picard; Arnau Montagud; Stéphane Liva; Alexandre Sta; Florent Dingli; Guillaume Arras; Jaime Rivera; Damarys Loew; Aurore Besnard; Joëlle Lacombe; Mélanie Pagès; Pascale Varlet; Christelle Dufour; Hua Yu; Audrey L Mercier; Emilie Indersie; Anaïs Chivet; Sophie Leboucher; Laura Sieber; Kevin Beccaria; Michael Gombert; Frauke D Meyer; Nan Qin; Jasmin Bartl; Lukas Chavez; Konstantin Okonechnikov; Tanvi Sharma; Venu Thatikonda; Franck Bourdeaut; Celio Pouponnot; Vijay Ramaswamy; Andrey Korshunov; Arndt Borkhardt; Guido Reifenberger; Patrick Poullet; Michael D Taylor; Marcel Kool; Stefan M Pfister; Daisuke Kawauchi; Emmanuel Barillot; Marc Remke; Olivier Ayrault

doi:10.1016/j.ccell.2018.08.002

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

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

Authors

Antoine Forget¹, Loredana Martignetti², Stéphanie Puget³, Laurence Calzone², Sebastian Brabetz⁴, Daniel Picard⁵, Arnau Montagud², Stéphane Liva², Alexandre Sta², Florent Dingli⁶, Guillaume Arras⁶, Jaime Rivera⁶, Damarys Loew⁶, Aurore Besnard⁷, Joëlle Lacombe⁷, Mélanie Pagès⁷, Pascale Varlet⁷, Christelle Dufour⁸, Hua Yu⁹, Audrey L Mercier⁹, Emilie Indersie⁹, Anaïs Chivet⁹, Sophie Leboucher¹⁰, Laura Sieber⁴, Kevin Beccaria³, Michael Gombert¹¹, Frauke D Meyer⁵, Nan Qin⁵, Jasmin Bartl⁵, Lukas Chavez⁴, Konstantin Okonechnikov⁴, Tanvi Sharma⁴, Venu Thatikonda⁴, Franck Bourdeaut¹², Celio Pouponnot⁹, Vijay Ramaswamy¹³, Andrey Korshunov¹⁴, Arndt Borkhardt¹¹, Guido Reifenberger¹⁵, Patrick Poullet², Michael D Taylor¹⁶, Marcel Kool⁴, Stefan M Pfister¹⁷, Daisuke Kawauchi¹⁸, Emmanuel Barillot¹⁹, Marc Remke²⁰, Olivier Ayrault²¹

Affiliations

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.

PMID: 30205043
DOI: 10.1016/j.ccell.2018.08.002

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.

Publication types

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

MeSH terms

Adolescent
Animals
Carcinogenesis / pathology
Cell Line, Tumor
Cerebellar Neoplasms / genetics
Cerebellar Neoplasms / pathology*
Cerebellum / pathology
Child
Child, Preschool
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Infant
Male
Medulloblastoma / genetics
Medulloblastoma / pathology*
Mice
Mice, Transgenic
Phosphorylation
Proteome / metabolism
Proteomics / methods
Receptor, ErbB-4 / metabolism*
Signal Transduction
src-Family Kinases / genetics
src-Family Kinases / metabolism*

Substances

Proteome
ERBB4 protein, human
Erbb4 protein, mouse
Receptor, ErbB-4
src-Family Kinases