Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

Tenley C. Archer; Tobias Ehrenberger; Filip Mundt; Maxwell P. Gold; Karsten Krug; Clarence K. Mah; Elizabeth L. Mahoney; Colin J. Daniel; Alexander LeNail; Divya Ramamoorthy; Philipp Mertins; D. R. Mani; Hailei Zhang; Michael A. Gillette; Karl Clauser; Michael Noble; Lauren C. Tang; Jessica Pierre-François; Jacob Silterra; James Jensen; Pablo Tamayo; Andrey Korshunov; Stefan M. Pfister; Marcel Kool; Paul A. Northcott; Rosalie C. Sears; Jonathan O. Lipton; Steven A. Carr; Jill P. Mesirov; Scott L. Pomeroy; Ernest Fraenkel

doi:10.1016/j.ccell.2018.08.004

Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

Tenley C. Archer, Tobias Ehrenberger, Filip Mundt, Maxwell P. Gold, Karsten Krug, Clarence K. Mah, Elizabeth L. Mahoney, Colin J. Daniel, Alexander LeNail, Divya Ramamoorthy, Philipp Mertins, D. R. Mani, Hailei Zhang, Michael A. Gillette, Karl Clauser, Michael Noble, Lauren C. Tang, Jessica Pierre-François, Jacob Silterra, James JensenPablo Tamayo, Andrey Korshunov, Stefan M. Pfister, Marcel Kool, Paul A. Northcott, Rosalie C. Sears, Jonathan O. Lipton, Steven A. Carr, Jill P. Mesirov, Scott L. Pomeroy, Ernest Fraenkel

Molecular & Medical Genetics

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

61 Scopus citations

Abstract

There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.

Original language	English (US)
Pages (from-to)	396-410.e8
Journal	Cancer Cell
Volume	34
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2018.08.004
State	Published - Sep 10 2018

Keywords

MYC
NU-7441
SHH
mass spectrometry
medulloblastoma
multi-omics
network integration
phospho-proteomics
proteo-genomics
radio sensitization

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2018.08.004

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Archer, T. C., Ehrenberger, T., Mundt, F., Gold, M. P., Krug, K., Mah, C. K., Mahoney, E. L., Daniel, C. J., LeNail, A., Ramamoorthy, D., Mertins, P., Mani, D. R., Zhang, H., Gillette, M. A., Clauser, K., Noble, M., Tang, L. C., Pierre-François, J., Silterra, J., ... Fraenkel, E. (2018). Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups. Cancer Cell, 34(3), 396-410.e8. https://doi.org/10.1016/j.ccell.2018.08.004

Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups. / Archer, Tenley C.; Ehrenberger, Tobias; Mundt, Filip; Gold, Maxwell P.; Krug, Karsten; Mah, Clarence K.; Mahoney, Elizabeth L.; Daniel, Colin J.; LeNail, Alexander; Ramamoorthy, Divya; Mertins, Philipp; Mani, D. R.; Zhang, Hailei; Gillette, Michael A.; Clauser, Karl; Noble, Michael; Tang, Lauren C.; Pierre-François, Jessica; Silterra, Jacob; Jensen, James; Tamayo, Pablo; Korshunov, Andrey; Pfister, Stefan M.; Kool, Marcel; Northcott, Paul A.; Sears, Rosalie C.; Lipton, Jonathan O.; Carr, Steven A.; Mesirov, Jill P.; Pomeroy, Scott L.; Fraenkel, Ernest.

In: Cancer Cell, Vol. 34, No. 3, 10.09.2018, p. 396-410.e8.

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

Archer, TC, Ehrenberger, T, Mundt, F, Gold, MP, Krug, K, Mah, CK, Mahoney, EL, Daniel, CJ, LeNail, A, Ramamoorthy, D, Mertins, P, Mani, DR, Zhang, H, Gillette, MA, Clauser, K, Noble, M, Tang, LC, Pierre-François, J, Silterra, J, Jensen, J, Tamayo, P, Korshunov, A, Pfister, SM, Kool, M, Northcott, PA, Sears, RC, Lipton, JO, Carr, SA, Mesirov, JP, Pomeroy, SL & Fraenkel, E 2018, 'Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups', Cancer Cell, vol. 34, no. 3, pp. 396-410.e8. https://doi.org/10.1016/j.ccell.2018.08.004

Archer, Tenley C. ; Ehrenberger, Tobias ; Mundt, Filip ; Gold, Maxwell P. ; Krug, Karsten ; Mah, Clarence K. ; Mahoney, Elizabeth L. ; Daniel, Colin J. ; LeNail, Alexander ; Ramamoorthy, Divya ; Mertins, Philipp ; Mani, D. R. ; Zhang, Hailei ; Gillette, Michael A. ; Clauser, Karl ; Noble, Michael ; Tang, Lauren C. ; Pierre-François, Jessica ; Silterra, Jacob ; Jensen, James ; Tamayo, Pablo ; Korshunov, Andrey ; Pfister, Stefan M. ; Kool, Marcel ; Northcott, Paul A. ; Sears, Rosalie C. ; Lipton, Jonathan O. ; Carr, Steven A. ; Mesirov, Jill P. ; Pomeroy, Scott L. ; Fraenkel, Ernest. / Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups. In: Cancer Cell. 2018 ; Vol. 34, No. 3. pp. 396-410.e8.

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title = "Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups",

abstract = "There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.",

keywords = "MYC, NU-7441, SHH, mass spectrometry, medulloblastoma, multi-omics, network integration, phospho-proteomics, proteo-genomics, radio sensitization",

author = "Archer, {Tenley C.} and Tobias Ehrenberger and Filip Mundt and Gold, {Maxwell P.} and Karsten Krug and Mah, {Clarence K.} and Mahoney, {Elizabeth L.} and Daniel, {Colin J.} and Alexander LeNail and Divya Ramamoorthy and Philipp Mertins and Mani, {D. R.} and Hailei Zhang and Gillette, {Michael A.} and Karl Clauser and Michael Noble and Tang, {Lauren C.} and Jessica Pierre-Fran{\c c}ois and Jacob Silterra and James Jensen and Pablo Tamayo and Andrey Korshunov and Pfister, {Stefan M.} and Marcel Kool and Northcott, {Paul A.} and Sears, {Rosalie C.} and Lipton, {Jonathan O.} and Carr, {Steven A.} and Mesirov, {Jill P.} and Pomeroy, {Scott L.} and Ernest Fraenkel",

note = "Funding Information: Funding: NIH/NCI U01-CA184898 (to E.F., J.P.M., and S.L.P.), NIH/NICHD U54-HD090255 (to S.L.P.), NIH/NCI R01-CA109467 (to S.L.P. and J.P.M.), NIH/NCI R01-CA121941 (to J.P.M.), NIH/NIGMS R01-GM074024 (to J.P.M.), NIH/NCI U24-CA194107 (to J.P.M.), NIH/NCI U24-CA210004 (to J.P.M.), NIH/NCI U01-CA217885 (to J.P.M. and P.T.), NIH/NCI R01-CA154480 (to P.T.), NIH/NCI U24-CA210986 (to S.A.C. and M.A.G.), NIH/NCI U24-CA210979 (to D.R.M.), NIH/NHLBI T32-HL007901 (to T.C.A.), NIH/NICHD 1U54HD090255 ( Boston Children's Hospital IDDRC ), NIH/NCI R01-CA196228 (to R.C.S.), NIH/NCI R01-CA186241 (to R.C.S.), NIH/NCI U54-CA209988 (to R.C.S.), Swedish Research Council Dnr 2014-323 (to F.M.), Swedish Society for Medical Research (to F.M.), AACR NextGen Grant for Transformative Cancer Research (to P.A.N.), American Lebanese Syrian Associated Charities (to P.A.N.), St. Jude Children's Research Hospital (to P.A.N.), and ICGC . Funding Information: Funding: NIH/NCI U01-CA184898 (to E.F., J.P.M., and S.L.P.), NIH/NICHD U54-HD090255 (to S.L.P.), NIH/NCI R01-CA109467 (to S.L.P. and J.P.M.), NIH/NCI R01-CA121941 (to J.P.M.), NIH/NIGMS R01-GM074024 (to J.P.M.), NIH/NCI U24-CA194107 (to J.P.M.), NIH/NCI U24-CA210004 (to J.P.M.), NIH/NCI U01-CA217885 (to J.P.M. and P.T.), NIH/NCI R01-CA154480 (to P.T.), NIH/NCI U24-CA210986 (to S.A.C. and M.A.G.), NIH/NCI U24-CA210979 (to D.R.M.), NIH/NHLBI T32-HL007901 (to T.C.A.), NIH/NICHD 1U54HD090255 (Boston Children's Hospital IDDRC), NIH/NCI R01-CA196228 (to R.C.S.), NIH/NCI R01-CA186241 (to R.C.S.), NIH/NCI U54-CA209988 (to R.C.S.), Swedish Research Council Dnr 2014-323 (to F.M.), Swedish Society for Medical Research (to F.M.), AACR NextGen Grant for Transformative Cancer Research (to P.A.N.), American Lebanese Syrian Associated Charities (to P.A.N.), St. Jude Children's Research Hospital (to P.A.N.), and ICGC. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = sep,

day = "10",

doi = "10.1016/j.ccell.2018.08.004",

language = "English (US)",

volume = "34",

pages = "396--410.e8",

journal = "Cancer Cell",

issn = "1535-6108",

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TY - JOUR

T1 - Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

AU - Archer, Tenley C.

AU - Ehrenberger, Tobias

AU - Mundt, Filip

AU - Gold, Maxwell P.

AU - Krug, Karsten

AU - Mah, Clarence K.

AU - Mahoney, Elizabeth L.

AU - Daniel, Colin J.

AU - LeNail, Alexander

AU - Ramamoorthy, Divya

AU - Mertins, Philipp

AU - Mani, D. R.

AU - Zhang, Hailei

AU - Gillette, Michael A.

AU - Clauser, Karl

AU - Noble, Michael

AU - Tang, Lauren C.

AU - Pierre-François, Jessica

AU - Silterra, Jacob

AU - Jensen, James

AU - Tamayo, Pablo

AU - Korshunov, Andrey

AU - Pfister, Stefan M.

AU - Kool, Marcel

AU - Northcott, Paul A.

AU - Sears, Rosalie C.

AU - Lipton, Jonathan O.

AU - Carr, Steven A.

AU - Mesirov, Jill P.

AU - Pomeroy, Scott L.

AU - Fraenkel, Ernest

N1 - Funding Information: Funding: NIH/NCI U01-CA184898 (to E.F., J.P.M., and S.L.P.), NIH/NICHD U54-HD090255 (to S.L.P.), NIH/NCI R01-CA109467 (to S.L.P. and J.P.M.), NIH/NCI R01-CA121941 (to J.P.M.), NIH/NIGMS R01-GM074024 (to J.P.M.), NIH/NCI U24-CA194107 (to J.P.M.), NIH/NCI U24-CA210004 (to J.P.M.), NIH/NCI U01-CA217885 (to J.P.M. and P.T.), NIH/NCI R01-CA154480 (to P.T.), NIH/NCI U24-CA210986 (to S.A.C. and M.A.G.), NIH/NCI U24-CA210979 (to D.R.M.), NIH/NHLBI T32-HL007901 (to T.C.A.), NIH/NICHD 1U54HD090255 ( Boston Children's Hospital IDDRC ), NIH/NCI R01-CA196228 (to R.C.S.), NIH/NCI R01-CA186241 (to R.C.S.), NIH/NCI U54-CA209988 (to R.C.S.), Swedish Research Council Dnr 2014-323 (to F.M.), Swedish Society for Medical Research (to F.M.), AACR NextGen Grant for Transformative Cancer Research (to P.A.N.), American Lebanese Syrian Associated Charities (to P.A.N.), St. Jude Children's Research Hospital (to P.A.N.), and ICGC . Funding Information: Funding: NIH/NCI U01-CA184898 (to E.F., J.P.M., and S.L.P.), NIH/NICHD U54-HD090255 (to S.L.P.), NIH/NCI R01-CA109467 (to S.L.P. and J.P.M.), NIH/NCI R01-CA121941 (to J.P.M.), NIH/NIGMS R01-GM074024 (to J.P.M.), NIH/NCI U24-CA194107 (to J.P.M.), NIH/NCI U24-CA210004 (to J.P.M.), NIH/NCI U01-CA217885 (to J.P.M. and P.T.), NIH/NCI R01-CA154480 (to P.T.), NIH/NCI U24-CA210986 (to S.A.C. and M.A.G.), NIH/NCI U24-CA210979 (to D.R.M.), NIH/NHLBI T32-HL007901 (to T.C.A.), NIH/NICHD 1U54HD090255 (Boston Children's Hospital IDDRC), NIH/NCI R01-CA196228 (to R.C.S.), NIH/NCI R01-CA186241 (to R.C.S.), NIH/NCI U54-CA209988 (to R.C.S.), Swedish Research Council Dnr 2014-323 (to F.M.), Swedish Society for Medical Research (to F.M.), AACR NextGen Grant for Transformative Cancer Research (to P.A.N.), American Lebanese Syrian Associated Charities (to P.A.N.), St. Jude Children's Research Hospital (to P.A.N.), and ICGC. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/9/10

Y1 - 2018/9/10

N2 - There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.

AB - There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies. Archer et al. quantitatively profile global proteomes of medulloblastomas (MB). They identify different pathways associated with subsets of SHH MB and post-translational modifications of MYC associated with poor outcomes in group 3 MB. Inhibition of PRKDC sensitizes MYC-driven cells to radiation.

KW - MYC

KW - NU-7441

KW - SHH

KW - mass spectrometry

KW - medulloblastoma

KW - multi-omics

KW - network integration

KW - phospho-proteomics

KW - proteo-genomics

KW - radio sensitization

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UR - http://www.scopus.com/inward/citedby.url?scp=85052155527&partnerID=8YFLogxK

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DO - 10.1016/j.ccell.2018.08.004

M3 - Article

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AN - SCOPUS:85052155527

VL - 34

SP - 396-410.e8

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -

Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

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Keywords

ASJC Scopus subject areas

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