Oncotarget

Research Papers:

Proteomic profiling of high risk medulloblastoma reveals functional biology

Jerome A. Staal, Ling San Lau, Huizhen Zhang, Wendy J. Ingram, Andrew R. Hallahan, Paul A. Northcott, Stefan M. Pfister, Robert J. Wechsler-Reya, Jessica M. Rusert, Michael D. Taylor, Yoon-Jae Cho, Roger J. Packer, Kristy J. Brown and Brian R. Rood _

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Oncotarget. 2015; 6:14584-14595. https://doi.org/10.18632/oncotarget.3927

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Abstract

Jerome A. Staal1, Ling San Lau1, Huizhen Zhang1, Wendy J. Ingram2, Andrew R. Hallahan2, Paul A. Northcott3, Stefan M. Pfister3, Robert J. Wechsler-Reya4, Jessica M. Rusert4, Michael D. Taylor5, Yoon-Jae Cho6, Roger J. Packer7, Kristy J. Brown8 and Brian R. Rood1

1 Center for Cancer and Immunology Research, Children’s National Medical Center, Washington DC, USA

2 UQ Child Health Research Centre, The University of Queensland and Queensland Children’s Medical Research Institute, Children’s Health, Queensland, Australia

3 Division of Pediatric Neurooncology, German Cancer Research Center, Heidleberg, Germany

4 Sanford-Burnham Medical Research Institute, La Jolla California, USA

5 Department of Neurosurgery, Hospital for Sick Children, Toronto, Canada

6 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, USA

7 Center for Neuroscience and Behavioral Medicine, Children’s National Medical Center, Washington DC, USA

8 Center for Genetic Medicine, Children’s National Medical Center, Washington DC, USA

Correspondence to:

Brian R. Rood, email:

Keywords: medulloblastoma; proteomics; cancer; cMYC; glycolysis

Received: April 03, 2015 Accepted: April 08, 2015 Published: April 23, 2015

Abstract

Genomic characterization of medulloblastoma has improved molecular risk classification but struggles to define functional biological processes, particularly for the most aggressive subgroups. We present here a novel proteomic approach to this problem using a reference library of stable isotope labeled medulloblastoma-specific proteins as a spike-in standard for accurate quantification of the tumor proteome. Utilizing high-resolution mass spectrometry, we quantified the tumor proteome of group 3 medulloblastoma cells and demonstrate that high-risk MYC amplified tumors can be segregated based on protein expression patterns. We cross-validated the differentially expressed protein candidates using an independent transcriptomic data set and further confirmed them in a separate cohort of medulloblastoma tissue samples to identify the most robust proteogenomic differences. Interestingly, highly expressed proteins associated with MYC-amplified tumors were significantly related to glycolytic metabolic pathways via alternative splicing of pyruvate kinase (PKM) by heterogeneous ribonucleoproteins (HNRNPs). Furthermore, when maintained under hypoxic conditions, these MYC-amplified tumors demonstrated increased viability compared to non-amplified tumors within the same subgroup. Taken together, these findings highlight the power of proteomics as an integrative platform to help prioritize genetic and molecular drivers of cancer biology and behavior.


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