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.
Highlights
Glioblastoma (GBM) is the most common brain tumor in adults and is associated with reduced life expectancy, ranging between 12 and 15 months 1
We showed that induced expression of intracellular fragment of ODZ1 (icODZ1) was followed by a specific increase in the mRNA levels of Ras homolog family member A (RhoA) but not Rac[1] or Cdc[42] (Figure 7a)
We showed that ODZ1 promotes actin cytoskeletal remodelling, migration and invasion of GBM stem-like cells (GSCs) as determined by using 2D and 3D in vitro systems, a xenograft model of chicken embryo and tumor specimens, in which ODZ1-expressing
Summary
Glioblastoma (GBM) is the most common brain tumor in adults and is associated with reduced life expectancy, ranging between 12 and 15 months 1. This aggressiveness is mostly due to the rapid growth and the invasive capacity of tumor cells. It has been demonstrated that GBM contains hierarchies with highly tumorigenic cells that display stem cell features 4. The Hedgehog family of proteins plays an instructional role during the development of many metazoans and is implicated in stem cell maintenance and tissue repair, and confers growth promoting and survival capabilities to cancer cells 9. Teneurins are philogenetically conserved type II transmembrane proteins located on the X-chromosome, is mainly expressed in the brain during the embryonic development nuclear localization signals, which may exert transcriptional regulation functions
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