Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Walderik W. Zomerman; Sabine L.A.  Plasschaert; Siobhan Conroy; Frank J. Scherpen; Tiny G.J. Meeuwsen-de Boer; Harm J. Lourens; Sergi Guerrero Llobet; Marlinde J. Smit; Lorian Slagter-Menkema; Annika Seitz; Corrie E.M. Gidding; Esther Hulleman; Pieter Wesseling; Lisethe Meijer; Leon C. van Kempen; Anke van den Berg; Daniel O. Warmerdam; Frank A.E. Kruyt; Floris Foijer; Marcel A.T.M. van Vugt; Wilfred F.A. den Dunnen; Eelco W. Hoving; Victor Guryev; Eveline S.J.M. de Bont; Sophia W.M. Bruggeman

doi:10.1016/j.celrep.2018.02.089

Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Walderik W. Zomerman, Sabine L.A. Plasschaert, Siobhan Conroy, Frank J. Scherpen, Tiny G.J. Meeuwsen-de Boer, Harm J. Lourens, Sergi Guerrero Llobet, Marlinde J. Smit, Lorian Slagter-Menkema, Annika Seitz, Corrie E.M. Gidding, Esther Hulleman, Pieter Wesseling, Lisethe Meijer, Leon C. van Kempen, Anke van den Berg, Daniel O. Warmerdam, Frank A.E. Kruyt, Floris Foijer, Marcel A.T.M. van VugtWilfred F.A. den Dunnen, Eelco W. Hoving, Victor Guryev, Eveline S.J.M. de Bont, Sophia W.M. Bruggeman

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

Original language	English
Pages (from-to)	3206-3216
Number of pages	10
Journal	Cell reports
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2018.02.089
Publication status	Published - 20 Mar 2018

Keywords

phosphoproteome
TP53
MYC
protein synthesis
medulloblastoma
protein-signaling
proteome

Access to Document

10.1016/j.celrep.2018.02.089

Cite this

Zomerman, W. W., Plasschaert, S. L. A., Conroy, S., Scherpen, F. J., Meeuwsen-de Boer, T. G. J., Lourens, H. J., Guerrero Llobet, S., Smit, M. J., Slagter-Menkema, L., Seitz, A., Gidding, C. E. M., Hulleman, E., Wesseling, P., Meijer, L., van Kempen, L. C., van den Berg, A., Warmerdam, D. O., Kruyt, F. A. E., Foijer, F., ... Bruggeman, S. W. M. (2018). Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma. Cell reports, 22(12), 3206-3216. https://doi.org/10.1016/j.celrep.2018.02.089

@article{ffdae3a6672943f986f565af9dbf9128,

title = "Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma",

abstract = "The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.",

keywords = "phosphoproteome, TP53, MYC, protein synthesis, medulloblastoma, protein-signaling, proteome",

author = "Zomerman, {Walderik W.} and Plasschaert, {Sabine L.A.} and Siobhan Conroy and Scherpen, {Frank J.} and {Meeuwsen-de Boer}, {Tiny G.J.} and Lourens, {Harm J.} and {Guerrero Llobet}, Sergi and Smit, {Marlinde J.} and Lorian Slagter-Menkema and Annika Seitz and Gidding, {Corrie E.M.} and Esther Hulleman and Pieter Wesseling and Lisethe Meijer and {van Kempen}, {Leon C.} and {van den Berg}, Anke and Warmerdam, {Daniel O.} and Kruyt, {Frank A.E.} and Floris Foijer and {van Vugt}, {Marcel A.T.M.} and {den Dunnen}, {Wilfred F.A.} and Hoving, {Eelco W.} and Victor Guryev and {de Bont}, {Eveline S.J.M.} and Bruggeman, {Sophia W.M.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s)",

year = "2018",

month = mar,

day = "20",

doi = "10.1016/j.celrep.2018.02.089",

language = "English",

volume = "22",

pages = "3206--3216",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "12",

}

Zomerman, WW, Plasschaert, SLA, Conroy, S, Scherpen, FJ, Meeuwsen-de Boer, TGJ, Lourens, HJ, Guerrero Llobet, S, Smit, MJ, Slagter-Menkema, L, Seitz, A, Gidding, CEM, Hulleman, E , Wesseling, P, Meijer, L, van Kempen, LC, van den Berg, A, Warmerdam, DO, Kruyt, FAE, Foijer, F, van Vugt, MATM, den Dunnen, WFA, Hoving, EW, Guryev, V, de Bont, ESJM & Bruggeman, SWM 2018, 'Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma', Cell reports, vol. 22, no. 12, pp. 3206-3216. https://doi.org/10.1016/j.celrep.2018.02.089

TY - JOUR

T1 - Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

AU - Zomerman, Walderik W.

AU - Plasschaert, Sabine L.A.

AU - Conroy, Siobhan

AU - Scherpen, Frank J.

AU - Meeuwsen-de Boer, Tiny G.J.

AU - Lourens, Harm J.

AU - Guerrero Llobet, Sergi

AU - Smit, Marlinde J.

AU - Slagter-Menkema, Lorian

AU - Seitz, Annika

AU - Gidding, Corrie E.M.

AU - Hulleman, Esther

AU - Wesseling, Pieter

AU - Meijer, Lisethe

AU - van Kempen, Leon C.

AU - van den Berg, Anke

AU - Warmerdam, Daniel O.

AU - Kruyt, Frank A.E.

AU - Foijer, Floris

AU - van Vugt, Marcel A.T.M.

AU - den Dunnen, Wilfred F.A.

AU - Hoving, Eelco W.

AU - Guryev, Victor

AU - de Bont, Eveline S.J.M.

AU - Bruggeman, Sophia W.M.

PY - 2018/3/20

Y1 - 2018/3/20

N2 - The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

AB - The brain cancer medulloblastoma consists of different transcriptional subgroups. To characterize medulloblastoma at the phosphoprotein-signaling level, we performed high-throughput peptide phosphorylation profiling on a large cohort of SHH (Sonic Hedgehog), group 3, and group 4 medulloblastomas. We identified two major protein-signaling profiles. One profile was associated with rapid death post-recurrence and resembled MYC-like signaling for which MYC lesions are sufficient but not necessary. The second profile showed enrichment for DNA damage, as well as apoptotic and neuronal signaling. Integrative analysis demonstrated that heterogeneous transcriptional input converges on these protein-signaling profiles: all SHH and a subset of group 3 patients exhibited the MYC-like protein-signaling profile; the majority of the other group 3 subset and group 4 patients displayed the DNA damage/apoptotic/neuronal signaling profile. Functional analysis of enriched pathways highlighted cell-cycle progression and protein synthesis as therapeutic targets for MYC-like medulloblastoma.

KW - phosphoproteome

KW - TP53

KW - MYC

KW - protein synthesis

KW - medulloblastoma

KW - protein-signaling

KW - proteome

UR - http://www.scopus.com/inward/record.url?scp=85044111819&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.02.089

DO - 10.1016/j.celrep.2018.02.089

M3 - Article

SN - 2211-1247

VL - 22

SP - 3206

EP - 3216

JO - Cell reports

JF - Cell reports

IS - 12

ER -

Identification of Two Protein-Signaling States Delineating Transcriptionally Heterogeneous Human Medulloblastoma

Abstract

Keywords

Access to Document

Fingerprint

Cite this