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

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. MercierEmilie 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

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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. 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.

Originele taal-2	Engels
Pagina's (van-tot)	379-395.e7
Tijdschrift	Cancer Cell
Volume	34
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1016/j.ccell.2018.08.002
Status	Gepubliceerd - 10 sep. 2018
Extern gepubliceerd	Ja

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10.1016/j.ccell.2018.08.002

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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., ... Ayrault, O. (2018). Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling. Cancer Cell, 34(3), 379-395.e7. https://doi.org/10.1016/j.ccell.2018.08.002

@article{ac9cd1a7aac442459f37768aed5f0354,

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

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. 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.",

keywords = "medulloblastoma, multi-omics, proteomics",

author = "Antoine Forget and Loredana Martignetti and St{\'e}phanie Puget and Laurence Calzone and Sebastian Brabetz and Daniel Picard and Arnau Montagud and St{\'e}phane Liva and Alexandre Sta and Florent Dingli and Guillaume Arras and Jaime Rivera and Damarys Loew and Aurore Besnard and Jo{\"e}lle Lacombe and M{\'e}lanie Pag{\`e}s and Pascale Varlet and Christelle Dufour and Hua Yu and Mercier, {Audrey L.} and Emilie Indersie and Ana{\"i}s Chivet and Sophie Leboucher and Laura Sieber and Kevin Beccaria and Michael Gombert and Meyer, {Frauke D.} and Nan Qin and Jasmin Bartl and Lukas Chavez and Konstantin Okonechnikov and Tanvi Sharma and Venu Thatikonda and Franck Bourdeaut and Celio Pouponnot and Vijay Ramaswamy and Andrey Korshunov and Arndt Borkhardt and Guido Reifenberger and Patrick Poullet and Taylor, {Michael D.} and Marcel Kool and Pfister, {Stefan M.} and Daisuke Kawauchi and Emmanuel Barillot and Marc Remke and Olivier Ayrault",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = sep,

day = "10",

doi = "10.1016/j.ccell.2018.08.002",

language = "English",

volume = "34",

pages = "379--395.e7",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

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 & Ayrault, O 2018, 'Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling', Cancer Cell, vol. 34, nr. 3, blz. 379-395.e7. https://doi.org/10.1016/j.ccell.2018.08.002

TY - JOUR

T1 - Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling

AU - Forget, Antoine

AU - Martignetti, Loredana

AU - Puget, Stéphanie

AU - Calzone, Laurence

AU - Brabetz, Sebastian

AU - Picard, Daniel

AU - Montagud, Arnau

AU - Liva, Stéphane

AU - Sta, Alexandre

AU - Dingli, Florent

AU - Arras, Guillaume

AU - Rivera, Jaime

AU - Loew, Damarys

AU - Besnard, Aurore

AU - Lacombe, Joëlle

AU - Pagès, Mélanie

AU - Varlet, Pascale

AU - Dufour, Christelle

AU - Yu, Hua

AU - Mercier, Audrey L.

AU - Indersie, Emilie

AU - Chivet, Anaïs

AU - Leboucher, Sophie

AU - Sieber, Laura

AU - Beccaria, Kevin

AU - Gombert, Michael

AU - Meyer, Frauke D.

AU - Qin, Nan

AU - Bartl, Jasmin

AU - Chavez, Lukas

AU - Okonechnikov, Konstantin

AU - Sharma, Tanvi

AU - Thatikonda, Venu

AU - Bourdeaut, Franck

AU - Pouponnot, Celio

AU - Ramaswamy, Vijay

AU - Korshunov, Andrey

AU - Borkhardt, Arndt

AU - Reifenberger, Guido

AU - Poullet, Patrick

AU - Taylor, Michael D.

AU - Kool, Marcel

AU - Pfister, Stefan M.

AU - Kawauchi, Daisuke

AU - Barillot, Emmanuel

AU - Remke, Marc

AU - Ayrault, Olivier

PY - 2018/9/10

Y1 - 2018/9/10

N2 - 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. 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.

AB - 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. 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.

KW - medulloblastoma

KW - multi-omics

KW - proteomics

UR - http://www.scopus.com/inward/record.url?scp=85052123474&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.08.002

DO - 10.1016/j.ccell.2018.08.002

M3 - Article

C2 - 30205043

AN - SCOPUS:85052123474

SN - 1535-6108

VL - 34

SP - 379-395.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

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