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

• Published in: Cancer cell Vol. 34; no. 3; pp. 379 - 395.e7
• Main Authors: Forget, Antoine, Martignetti, Loredana, Puget, Stéphanie, Calzone, Laurence, Brabetz, Sebastian, Picard, Daniel, Montagud, Arnau, Liva, Stéphane, Sta, Alexandre, Dingli, Florent, Arras, Guillaume, Rivera, Jaime, Loew, Damarys, Besnard, Aurore, Lacombe, Joëlle, Pagès, Mélanie, Varlet, Pascale, Dufour, Christelle, Yu, Hua, Mercier, Audrey L., Indersie, Emilie, Chivet, Anaïs, Leboucher, Sophie, Sieber, Laura, Beccaria, Kevin, Gombert, Michael, Meyer, Frauke D., Qin, Nan, Bartl, Jasmin, Chavez, Lukas, Okonechnikov, Konstantin, Sharma, Tanvi, Thatikonda, Venu, Bourdeaut, Franck, Pouponnot, Celio, Ramaswamy, Vijay, Korshunov, Andrey, Borkhardt, Arndt, Reifenberger, Guido, Poullet, Patrick, Taylor, Michael D., Kool, Marcel, Pfister, Stefan M., Kawauchi, Daisuke, Barillot, Emmanuel, Remke, Marc, Ayrault, Olivier
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2018; Elsevier
• Subjects: Adolescent; Animals; Cancer; 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; Life Sciences; Male; medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - pathology; Mice; Mice, Transgenic; multi-omics; Phosphorylation; Proteome - metabolism; proteomics; Proteomics - methods; Receptor, ErbB-4 - metabolism; Signal Transduction; src-Family Kinases - genetics; src-Family Kinases - metabolism; proteomics; multi-omics; medulloblastoma
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2018.08.002

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. [Display omitted] •Highly divergent posttranscriptional pathway regulation in MB subgroups•Phosphoproteomic profiles reveal specific kinase activity in MB subgroups•Identification of aberrant ERBB4-SRC signaling as a hallmark of group 4 MBs•Over expression of activated SRC in the developing cerebellum induces MB Using proteomic analyses, Forget et al. unravel divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas (MB) and identify aberrant ERBB4-SRC signaling in group 4. Expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 MB.