1. Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.
- Author
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Forget A, Martignetti L, Puget S, Calzone L, Brabetz S, Picard D, Montagud A, Liva S, Sta A, Dingli F, Arras G, Rivera J, Loew D, Besnard A, Lacombe J, Pagès M, Varlet P, Dufour C, Yu H, Mercier AL, Indersie E, Chivet A, Leboucher S, Sieber L, Beccaria K, Gombert M, Meyer FD, Qin N, Bartl J, Chavez L, Okonechnikov K, Sharma T, Thatikonda V, Bourdeaut F, Pouponnot C, Ramaswamy V, Korshunov A, Borkhardt A, Reifenberger G, Poullet P, Taylor MD, Kool M, Pfister SM, Kawauchi D, Barillot E, Remke M, and Ayrault O
- Subjects
- Adolescent, Animals, Carcinogenesis pathology, Cell Line, Tumor, Cerebellar Neoplasms genetics, Cerebellum pathology, Child, Child, Preschool, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Medulloblastoma genetics, Mice, Mice, Transgenic, Phosphorylation, Proteome metabolism, Proteomics methods, Signal Transduction, src-Family Kinases genetics, Cerebellar Neoplasms pathology, Medulloblastoma pathology, Receptor, ErbB-4 metabolism, src-Family Kinases metabolism
- 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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