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

Cancer Cell. 2018 Sep 10;34(3):396-410.e8. doi: 10.1016/j.ccell.2018.08.004.

Authors

Tenley C Archer¹, Tobias Ehrenberger², Filip Mundt³, Maxwell P Gold², Karsten Krug⁴, Clarence K Mah⁵, Elizabeth L Mahoney⁶, Colin J Daniel⁷, Alexander LeNail², Divya Ramamoorthy², Philipp Mertins⁴, D R Mani⁴, Hailei Zhang⁴, Michael A Gillette⁸, Karl Clauser⁴, Michael Noble⁴, Lauren C Tang⁴, Jessica Pierre-François⁶, Jacob Silterra⁴, James Jensen⁵, Pablo Tamayo⁹, Andrey Korshunov¹⁰, Stefan M Pfister¹¹, Marcel Kool¹², Paul A Northcott¹³, Rosalie C Sears⁷, Jonathan O Lipton¹⁴, Steven A Carr¹⁵, Jill P Mesirov¹⁶, Scott L Pomeroy¹⁷, Ernest Fraenkel¹⁸

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
³ Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
⁴ Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA.
⁶ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁷ Department of Molecular and Medical Genetics, Oregon Health and Science University (OHSU), Portland, OR, USA.
⁸ Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
⁹ Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA.
¹⁰ CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, Heidelberg University, Heidelberg, Germany.
¹¹ Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
¹² Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
¹³ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
¹⁴ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
¹⁵ Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: scarr@broadinstitute.org.
¹⁶ Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA; Moores Cancer Center, University of California San Diego (UCSD), La Jolla, CA, USA. Electronic address: jmesirov@ucsd.edu.
¹⁷ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: scott.pomeroy@childrens.harvard.edu.
¹⁸ Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Electronic address: fraenkel-admin@mit.edu.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Biomarkers, Tumor / metabolism*
Brain Neoplasms / pathology*
Cell Line, Tumor
Child
Child, Preschool
DNA Methylation
DNA-Activated Protein Kinase / metabolism
Female
Gene Expression Profiling
Hedgehog Proteins / metabolism
Humans
Infant
Male
Medulloblastoma / pathology*
Nuclear Proteins / metabolism
Protein Processing, Post-Translational*
Proteome / metabolism
Proteomics
Proto-Oncogene Proteins c-myc / metabolism
Sequence Analysis, RNA
Young Adult

Substances

Biomarkers, Tumor
Hedgehog Proteins
MYC protein, human
Nuclear Proteins
Proteome
Proto-Oncogene Proteins c-myc
SHH protein, human
DNA-Activated Protein Kinase
PRKDC protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding