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

Publication date: 10 September 2018Source: Cancer Cell, Volume 34, Issue 3Author(s): 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. MercierSummaryThe 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research