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ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA

Oncogene volume 36, pages 1733–1744 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by the Instituto de Salud Carlos III (ISCIII), grants PI13/01760 (JLF-L), PI12/00775 (PS-G) and SAF2014-53526R (JL), and program Red Temática de Investigación Cooperativa en Cáncer (RTICC) grants RD12/0036/0022 (JLF-L), RD12/0036/0027 (PS-G), RD12/0036/0063 (JAM-C), RD12/0036/0003 (AP) and RD12-0036-0033 (JL), Instituto de Investigación Valdecilla (IDIVAL) grant APG/03 to JLF-L, and Cancer Research UK C33043/A12065 and Royal Society RG110591 to VS-M. We thank R. Galli for kindly providing RG1 cell line. We also thank M.E. Fernández-Valle for helping with magnetic resonance imaging experiments.

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Authors and Affiliations

  1. Unidad de Genética, Hospital Valdecilla-IDIVAL, Santander, Spain

    A Talamillo, L Grande, P Ruiz-Ontañon, P Mollinedo, S Torices & J L Fernandez-Luna

  2. Servicio de Neurocirugía, Hospital Valdecilla-IDIVAL, Santander, Spain

    C Velasquez & A Vazquez-Barquero

  3. Unidad de Neuro-Oncología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    P Sanchez-Gomez

  4. Centro para la Investigación Médica Aplicada (CIMA), Pamplona, Spain

    A Aznar, V Segura & J A Martinez-Climent

  5. Centro de Investigación del Cáncer (CSIC-USAL), Salamanca, Spain

    A Esparis-Ogando & A Pandiella

  6. Servicio de Oncología Médica, Hospital Valdecilla-IDIVAL, Santander, Spain

    C Lopez-Lopez

  7. Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, Santander, Spain

    C Lafita & J Leon

  8. Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain

    M T Berciano, J A Montero & M Lafarga

  9. Servicio de Anatomía Patológica, Hospital Valdecilla and Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain

    N T Villagra

  10. Randall Division of Cell and Molecular Biophysics, School of Biomedical and Health Sciences, King's College London, London, UK

    V Sanz-Moreno

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Correspondence to J L Fernandez-Luna.

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Talamillo, A., Grande, L., Ruiz-Ontañon, P. et al. ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA. Oncogene 36, 1733–1744 (2017). https://doi.org/10.1038/onc.2016.341

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