title: Proteomic profiling of high risk medulloblastoma reveals functional biology.
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.
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington DC, USA.
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Staal
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington DC, USA.
authors.forename: Ling San
authors.initials: LS
authors.lastname: Lau
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington DC, USA.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: UQ Child Health Research Centre, The University of Queensland and Queensland Children's Medical Research Institute, Children's Health, Queensland, Australia.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Ingram
authors.affiliation: UQ Child Health Research Centre, The University of Queensland and Queensland Children's Medical Research Institute, Children's Health, Queensland, Australia.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hallahan
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center, Heidleberg, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center, Heidleberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Rusert
authors.affiliation: Department of Neurosurgery, Hospital for Sick Children, Toronto, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington DC, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.affiliation: Center for Genetic Medicine, Children's National Medical Center, Washington DC, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.affiliation: Center for Cancer and Immunology Research, Children's National Medical Center, Washington DC, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rood
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D013058:Mass Spectrometry; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: cMYC; cancer; glycolysis; medulloblastoma; proteomics