Neuropilin-1 modulates the 3D invasive properties of glioblastoma stem-like cells

Abstract

Glioblastoma multiforme (GBM) is a rare, yet devastating, primary brain tumor in adults. Current treatments remain generally ineffective and GBM almost invariably recurs, resulting in median survival of 15 months. This high malignancy sources notably from the resilience and invasive capabilities of tumor cells. Within GBM, exists a population of self-sustaining transformed cells with stem-like properties (GSCs), which are thought to be responsible for tumor initiation, growth, and invasion, as well as recurrence. In the tumor microenvironment, GSCs might be found in the vicinity of brain endothelial cells, which provide a protective habitat. Likewise, these resistant, quiescent GSCs may accumulate in hypoxic zones, away from the perivascular niche, or travel towards the healthy brain parenchyma, by eminently co-opting neuro-vascular tracks. Herein, we established an ex vivo model to explore GSC invasive behavior. We found that patient-derived cells massively invade the collagen matrix. In addition, we described that the glycoprotein Neuropilin-1 (NRP1) contributes to GSC spreading and invasion. Indeed, both RNA interference-mediated silencing and CRISPR-mediated gene editing deletion of NRP1 strongly impaired the 3D invasive properties of patient-derived GSCs and their close localization to the brain blood vessels. Of note, other typical features of GSCs, such as expansion and self-renewal were maintained. From a mechanistic standpoint, this biological effect might rely on the expression of the β3 subunit integrin cell-extracellular matrix adhesive receptor. Our data, therefore, propose a reliable approach to explore invasive properties of patient glioma cells ex vivo and identify NRP1 as a mediator in this malignant process.

VEGFA/NRP-1/GAPVD1 axis promotes progression and cancer stemness of triple-negative breast cancer by enhancing tumor cell-macrophage crosstalk

“…Grun et al 22 found that VEGFA acted via NRP-1 to enhance epidermal CSC survival and the formation of aggressive and highly vascularized tumors. Mathilde et al 39 found that NRP-1 modulated the 3D invasive properties of glioblastoma stem-like cells, and both RNA interference-mediated silencing and CRISPR-mediated gene editing deletion of NRP-1 strongly impaired the 3D invasive properties of patient-derived cells with stem-like properties and their close localization to brain blood vessels. Another study reported that NRP-1 was overexpressed in medulloblastoma (MB) and related to the undifferentiated status of MB and that an NRP-1 inhibitor (MR438) could stimulate the differentiation of MB stem-like cells.…”

The Nervous System Development Regulator Neuropilin-1 as a Potential Prognostic Marker and Therapeutic Target in Brain Cancer

“…Both RNA interference-mediated silencing and CRISPR-mediated gene editing deletion of NRP1 strongly impair the invasive capacity of properties of patient-derived GBM BTSCs and their close localization to brain blood vessels without affecting BTSC expansion and self-renewal. These actions of NRP1 in BTSCs may depend on the expression of the β3 subunit integrin cell-extracellular matrix adhesive receptor [101] RT-PCR of 37 glioma specimens, out of which 17 were grade IV GBM tumors, showed that NRP1 mRNA expression is higher in GBM than in non-tumoral tissue and lower-grade gliomas, and glioma patients with NRP1 overexpression (56.8%) showed a poorer prognosis indicated by reduced overall survival [102]. Moreover, NRP1 is an independent risk factor for both survival and recurrence in patients with GBMs, and high NRP1 mRNA expression is associated with shorter overall and disease-free survival, as shown by analysis of The Cancer Genome Atlas (TCGA) dataset [93].…”

NRP1 Induces Enhanced Stemness and Chemoresistance in Glioma Cells <i>via</i> YAP

“…18) Studies have confirmed that NRP1 is a critical molecule in regulating the invasive capacity of glioblastoma stem-like cells in vitro. 19) It has also been found that NRP1 is associated with TMZ resistance in glioblastoma. 20) However, whether NRP1 regulates the stemness and chemoresistance of glioma cells through YAP is unclear.…”