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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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Oncogene. 2017 Mar 23;36(12):1733-1744

Editorial: Basingstoke : Nature Publishing Group

 Fecha de publicación: 23/03/2017

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/onc.2016.341

ISSN: 0950-9232,1476-5594

Autores/as

ANA TALAMILLO CANCELO

LARA GRANDE GONZALEZ

RUIZ ONTAÑÓN, PATRICIA

CARLOS JOSE VELASQUEZ RODRIGUEZ

MOLLINEDO, PILAR

SILVIA TORICES DEL VAL

SÁNCHEZ GÓMEZ, PILAR

AZNAR, ÁNGELA

ESPARIS OGANDO, AZUCENA

LÓPEZ LÓPEZ, CARLOS

MARIA DEL CARMEN LAFITA NAVARRO

MARIA TERESA BERCIANO BLANCO

ALFONSO VAZQUEZ BARQUERO

SEGURA, VÍCTOR

VILLAGRA, NURIA T.

PANDIELLA, ATANASIO

MIGUEL ANGEL LAFARGA COSCOJUELA

MARTÍNEZ CLIMENT, JOSÉ A.

SANZ MORENO, VICTORIA

JOSE LUIS FERNANDEZ LUNA