Metabolic/Proteomic Signature Defines Two Glioblastoma Subtypes With Different Clinical Outcome

Glioblastoma (GBM) is one of the deadliest human cancers. Because of the extremely unfavorable prognosis of GBM, it is important to develop more effective diagnostic and therapeutic strategies based on biologically and clinically relevant subclassification systems. Analyzing a collection of seventeen patient-derived glioblastoma stem-like cells (GSCs) by gene expression profiling, NMR spectroscopy and signal transduction pathway activation, we identified two GSC clusters, one characterized by a pro-neural-like phenotype and the other showing a mesenchymal-like phenotype. Evaluating the levels of proteins differentially expressed by the two GSC clusters in the TCGA GBM sample collection, we found that SRC activation is associated with a GBM subgroup showing better prognosis whereas activation of RPS6, an effector of mTOR pathway, identifies a subgroup with a worse prognosis. The two clusters are also differentiated by NMR spectroscopy profiles suggesting a potential prognostic stratification based on metabolic evaluation. Our data show that the metabolic/proteomic profile of GSCs is informative of the genomic/proteomic GBM landscape, which differs among tumor subtypes and is associated with clinical outcome.

[1]  Michael Sabel,et al.  Genomic and Expression Profiling of Glioblastoma Stem Cell–Like Spheroid Cultures Identifies Novel Tumor-Relevant Genes Associated with Survival , 2009, Clinical Cancer Research.

[2]  Angelo L. Vescovi,et al.  Brain tumour stem cells , 2006, Nature Reviews Cancer.

[3]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[4]  M. Westphal,et al.  A distinct subset of glioma cell lines with stem cell‐like properties reflects the transcriptional phenotype of glioblastomas and overexpresses CXCR4 as therapeutic target , 2011, Glia.

[5]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[6]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[7]  P. Collas,et al.  Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. , 2005, Molecular biology of the cell.

[8]  L. Ricci-Vitiani,et al.  1H NMR detects different metabolic profiles in glioblastoma stem‐like cells , 2014, NMR in biomedicine.

[9]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[10]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Kylie L. Gorringe,et al.  Are there any more ovarian tumor suppressor genes? A new perspective using ultra high‐resolution copy number and loss of heterozygosity analysis , 2009, Genes, chromosomes & cancer.

[12]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[13]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[14]  A. Levine,et al.  The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses , 2013, Cell Death and Differentiation.

[15]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[16]  M. Westphal,et al.  Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria , 2008, Oncogene.

[17]  M. Okada,et al.  Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells. , 2014, Stem cell research.

[18]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[19]  L. Ricci-Vitiani,et al.  Cancer Stem Cell Analysis and Clinical Outcome in Patients with Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[20]  Prahlad T. Ram,et al.  A pan-cancer proteomic perspective on The Cancer Genome Atlas , 2014, Nature Communications.

[21]  R. McLendon,et al.  Integrin alpha 6 regulates glioblastoma stem cells. , 2010, Cell stem cell.

[22]  H Straatman,et al.  Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines , 2006, Oncogene.

[23]  Rolf Gruetter,et al.  1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: improvements in quantification of the neurochemical profile. , 2008, Journal of magnetic resonance.

[24]  Thomas M. Harris,et al.  Hypermethylation of a cluster of Krüppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal squamous cell carcinoma. , 2011, The American journal of pathology.

[25]  R. Wilson,et al.  Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. , 2010, Cancer cell.

[26]  Yuri Kotliarov,et al.  Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. , 2006, Cancer cell.

[27]  L. Deangelis,et al.  Virchow 2011 or how to ID(H) human glioblastoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  Tzong-Shiue Yu,et al.  A restricted cell population propagates glioblastoma growth after chemotherapy , 2012 .

[29]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

[30]  N. Potter,et al.  Genetic and Functional Diversity of Propagating Cells in Glioblastoma , 2014, Stem cell reports.

[31]  Jeffrey R. Whiteaker,et al.  Proteogenomic characterization of human colon and rectal cancer , 2014, Nature.

[32]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[33]  B. Chabner.  Early accelerated approval for highly targeted cancer drugs. , 2011, The New England journal of medicine.

[34]  S. Vacher,et al.  Differential Distribution of erbB Receptors in Human Glioblastoma Multiforme: Expression of erbB3 in CD133-Positive Putative Cancer Stem Cells , 2010, Journal of neuropathology and experimental neurology.

[35]  P. Larson,et al.  Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma. , 2014, Cancer research.

[36]  Zhaoshi Jiang,et al.  Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  L. Ricci-Vitiani,et al.  Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis , 2013, Cancer.

[38]  Shawn M. Gillespie,et al.  Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma , 2014, Science.

[39]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[40]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[41]  F. Zanoguera,et al.  Convergent Functional Genomics of Oligodendrocyte Differentiation Identifies Multiple Autoinhibitory Signaling Circuits , 2009, Molecular and Cellular Biology.

[42]  Eran Segal,et al.  Module map of stem cell genes guides creation of epithelial cancer stem cells. , 2008, Cell stem cell.

[43]  R. Gruetter,et al.  Improvements in quantification of the neurochemical profile , 2008 .

[44]  K. Camphausen,et al.  Visualizing Molecular Profiles of Glioblastoma with GBM-BioDP , 2014, PloS one.

[45]  Christopher Nimsky,et al.  Preoperative grading of gliomas by using metabolite quantification with high-spatial-resolution proton MR spectroscopic imaging. , 2006, Radiology.

[46]  Lynda Chin,et al.  Emerging insights into the molecular and cellular basis of glioblastoma. , 2012, Genes & development.

[47]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[48]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[49]  D. Xie,et al.  Downregulation of the novel tumor suppressor DIRAS1 predicts poor prognosis in esophageal squamous cell carcinoma. , 2013, Cancer research.

[50]  L. Ricci-Vitiani,et al.  Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo , 2014, Cell Death and Disease.

[51]  J K Smith,et al.  Correlation of myo-inositol levels and grading of cerebral astrocytomas. , 2000, AJNR. American journal of neuroradiology.

[52]  Franklyn A Howe,et al.  An investigation of human brain tumour lipids by high‐resolution magic angle spinning 1H MRS and histological analysis , 2008, NMR in biomedicine.