title: ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA.
abstract: Long-term survival remains low for most patients with glioblastoma (GBM), which reveals the need for markers of disease outcome and novel therapeutic targets. We describe that ODZ1 (also known as TENM1), a type II transmembrane protein involved in fetal brain development, plays a crucial role in the invasion of GBM cells. Differentiation of glioblastoma stem-like cells drives the nuclear translocation of an intracellular fragment of ODZ1 through proteolytic cleavage by signal peptide peptidase-like 2a. The intracellular fragment of ODZ1 promotes cytoskeletal remodelling of GBM cells and invasion of the surrounding environment both in vitro and in vivo. Absence of ODZ1 by gene deletion or downregulation of ODZ1 by small interfering RNAs drastically reduces the invasive capacity of GBM cells. This activity is mediated by an ODZ1-triggered transcriptional pathway, through the E-box binding Myc protein, that promotes the expression and activation of Ras homolog family member A (RhoA) and subsequent activation of Rho-associated, coiled-coil containing protein kinase (ROCK). Overexpression of ODZ1 in GBM cells reduced survival of xenografted mice. Consistently, analysis of 122 GBM tumour samples revealed that the number of ODZ1-positive cells inversely correlated with overall and progression-free survival. Our findings establish a novel marker of invading GBM cells and consequently a potential marker of disease progression and a therapeutic target in GBM.
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Talamillo
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Grande
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Ruiz-Ontañon
authors.affiliation: Servicio de Neurocirugía, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Velasquez
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Mollinedo
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Torices
authors.affiliation: Unidad de Neuro-Oncología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Sanchez-Gomez
authors.affiliation: Centro para la Investigación Médica Aplicada (CIMA), Pamplona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Aznar
authors.affiliation: Centro de Investigación del Cáncer (CSIC-USAL), Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Esparis-Ogando
authors.affiliation: Servicio de Oncología Médica, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Lopez-Lopez
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Lafita
authors.affiliation: Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Berciano
authors.affiliation: Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Montero
authors.affiliation: Servicio de Neurocirugía, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Vazquez-Barquero
authors.affiliation: Centro para la Investigación Médica Aplicada (CIMA), Pamplona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Segura
authors.affiliation: Servicio de Anatomía Patológica, Hospital Valdecilla and Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
authors.forename: N T
authors.initials: NT
authors.lastname: Villagra
authors.affiliation: Centro de Investigación del Cáncer (CSIC-USAL), Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Lafarga
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Leon
authors.affiliation: Centro para la Investigación Médica Aplicada (CIMA), Pamplona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Martinez-Climent
authors.affiliation: Randall Division of Cell and Molecular Biophysics, School of Biomedical and Health Sciences, King's College London, London, UK.
authors.forename: V
authors.identifier: 0000-0002-5096-9456
authors.initials: V
authors.lastname: Sanz-Moreno
authors.affiliation: Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Fernandez-Luna
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D021381:Protein Transport; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D019063:Tenascin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D019063:Tenascin; C120530:teneurin-1; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein