The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E‐box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1‐miR‐200 feedback loop interconnects these processes through the downstream effectors ROBO1, c‐MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial‐mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.

[1]  G. Nikkhah,et al.  Activation of canonical WNT/β-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition. , 2012, Cancer letters.

[2]  Jishu Shi,et al.  IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation , 2012, Molecular Cancer.

[3]  D. Cheresh,et al.  VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. , 2012, Cancer cell.

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

[5]  B. Calabretta,et al.  TGFβ-induced c-Myb affects the expression of EMT-associated genes and promotes invasion of ER+ breast cancer cells , 2011, Cell cycle.

[6]  I. Haviv,et al.  The social aspects of EMT-MET plasticity , 2011, Nature Medicine.

[7]  H. Fine,et al.  Effect of brain- and tumor-derived connective tissue growth factor on glioma invasion. , 2011, Journal of the National Cancer Institute.

[8]  C. Brennan,et al.  Molecular subclassification of diffuse gliomas: Seeing order in the chaos , 2011, Glia.

[9]  D. Steindler,et al.  The origins of glioma: E Pluribus Unum? , 2011, Glia.

[10]  H. Fine,et al.  Cancer stem cells in gliomas: Identifying and understanding the apex cell in cancer's hierarchy , 2011, Glia.

[11]  Michael Platten,et al.  Pathway inhibition: emerging molecular targets for treating glioblastoma. , 2011, Neuro-oncology.

[12]  J. Rich,et al.  Deadly teamwork: neural cancer stem cells and the tumor microenvironment. , 2011, Cell stem cell.

[13]  A. Vescovi,et al.  Evidence for label-retaining tumour-initiating cells in human glioblastoma. , 2011, Brain : a journal of neurology.

[14]  Qiulian Wu,et al.  Elevated invasive potential of glioblastoma stem cells. , 2011, Biochemical and biophysical research communications.

[15]  R. Weinberg,et al.  A Perspective on Cancer Cell Metastasis , 2011, Science.

[16]  Ian M. Carr,et al.  MethylViewer: computational analysis and editing for bisulfite sequencing and methyltransferase accessibility protocol for individual templates (MAPit) projects , 2010, Nucleic Acids Res..

[17]  B. Necela,et al.  Misregulated E-Cadherin Expression Associated with an Aggressive Brain Tumor Phenotype , 2010, PloS one.

[18]  Simone Brabletz,et al.  The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? , 2010, EMBO reports.

[19]  J. Settleman,et al.  EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer , 2010, Oncogene.

[20]  D. Steindler,et al.  Residual tumor cells are unique cellular targets in glioblastoma , 2010, Annals of neurology.

[21]  G. Bernier,et al.  BMI1 Confers Radioresistance to Normal and Cancerous Neural Stem Cells through Recruitment of the DNA Damage Response Machinery , 2010, The Journal of Neuroscience.

[22]  Richard Beyer,et al.  TWIST1 promotes invasion through mesenchymal change in human glioblastoma , 2010, Molecular Cancer.

[23]  M. Herlyn,et al.  Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. , 2010, Cancer research.

[24]  Serban Nacu,et al.  A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. , 2010, Cancer cell.

[25]  Yuan Qi,et al.  Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA , IDH 1 , EGFR , and NF 1 Citation Verhaak , 2010 .

[26]  R. Huang,et al.  Epithelial-Mesenchymal Transitions in Development and Disease , 2009, Cell.

[27]  Julia Schüler,et al.  The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs , 2009, Nature Cell Biology.

[28]  C. Brennan,et al.  Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations , 2009, PloS one.

[29]  I. Blümcke,et al.  Spontaneous In Vitro Transformation of Adult Neural Precursors into Stem‐Like Cancer Cells , 2009, Brain pathology.

[30]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[31]  Zhiwei Wang,et al.  Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. , 2009, Cancer research.

[32]  Tatsuya Ozawa,et al.  PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. , 2009, Cell stem cell.

[33]  Paolo Malatesta,et al.  SOX2 Silencing in Glioblastoma Tumor‐Initiating Cells Causes Stop of Proliferation and Loss of Tumorigenicity , 2009, Stem cells.

[34]  Simone Brabletz,et al.  E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer , 2009, Cancer and Metastasis Reviews.

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

[36]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[37]  E. Domany,et al.  Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[39]  J. Geng,et al.  Slit2 involvement in glioma cell migration is mediated by Robo1 receptor , 2008, Journal of Neuro-Oncology.

[40]  M. Berens,et al.  Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. , 2007, Journal of the National Cancer Institute.

[41]  Paolo Vicini,et al.  Predicting Human Tumor Drug Concentrations from a Preclinical Pharmacokinetic Model of Temozolomide Brain Disposition , 2007, Clinical Cancer Research.

[42]  Hongye Liu,et al.  Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant Glioma , 2007, Neuron.

[43]  M. Berens,et al.  Molecular targets of glioma invasion , 2007, Cellular and Molecular Life Sciences.

[44]  G. Broggi,et al.  Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells , 2006, Nature.

[45]  Mark W. Dewhirst,et al.  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response , 2006, Nature.

[46]  D. Steindler,et al.  Neurogenic astrocytes transplanted into the adult mouse lateral ventricle contribute to olfactory neurogenesis, and reveal a novel intrinsic subependymal neuron , 2006, Neuroscience.

[47]  Margaret Wrensch,et al.  Epidemiology and molecular pathology of glioma , 2006, Nature Clinical Practice Neurology.

[48]  I. Blümcke,et al.  Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases , 2006, Acta Neuropathologica.

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

[50]  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.

[51]  R. Kiss,et al.  Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[53]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[54]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[55]  Qihong Zhou,et al.  Correlation of N-cadherin expression in high grade gliomas with tissue invasion , 2004, Journal of Neuro-Oncology.

[56]  S. Gerson.  MGMT: its role in cancer aetiology and cancer therapeutics , 2004, Nature Reviews Cancer.

[57]  K. Fujii,et al.  Relationship between the Expression of E-, N-cadherins and beta-catenin and Tumor Grade in Astrocytomas , 2002, Journal of Neuro-Oncology.

[58]  P. Dirks.  Glioma Migration: Clues from the Biology of Neural Progenitor Cells and Embryonic CNS Cell Migration , 2001, Journal of Neuro-Oncology.

[59]  J. S. Rao,et al.  Molecular mechanisms of glioma invasiveness: the role of proteases , 2003, Nature Reviews Cancer.

[60]  J. Lilien,et al.  Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion , 2002, Nature Cell Biology.

[61]  D. Steindler,et al.  Human cortical glial tumors contain neural stem‐like cells expressing astroglial and neuronal markers in vitro , 2002, Glia.

[62]  S. Finkelstein,et al.  Multifaceted resistance of gliomas to temozolomide. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  J. Lilien,et al.  Rhee, J. et al. Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion. Nat. Cell Biol. 4, 798-805 , 2002 .

[64]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[65]  David Ghosh,et al.  Object oriented Transcription Factors Database (ooTFD) , 1999, Nucleic Acids Res..

[66]  S. Coons,et al.  Dichotomy of astrocytoma migration and proliferation , 1996, International journal of cancer.

[67]  K. Sakumi,et al.  Intracellular localization and function of DNA repair methyltransferase in human cells. , 1994, Mutation research.

[68]  C. Wilson.  Glioblastoma: the past, the present, and the future. , 1992, Clinical neurosurgery.

[69]  Wilson Cb.  Glioblastoma: the past, the present, and the future. , 1992 .

[70]  M. Clarke,et al.  Constitutive expression of a c-myb cDNA blocks Friend murine erythroleukemia cell differentiation. , 1988, Molecular and cellular biology.