SOAP Box picture 2021 full.jpeg

SOAP: Signaling in Oncogenesis, Angiogenesis, and Permeability

On the ground of our interests for molecular piracy exerted by tumor cells to survive, adapt and remodel their environment, we explore the signaling mechanisms involved in non-oncogene addiction and loss of vascular homeostasis.

  • Wix Twitter page
  • Facebook Social Icon
  • Instagram

Latest News

Crayon et bloc-notes
Crayon et bloc-notes
anr-logo-2021-complet_edited.jpg
Neuropilin-1 in GBM

Kerherve et al.,  Front Cell Dev Biol 2022
 MLKL in GBM

Andre-Gregoire et al., iScience 2022
 New grant in the lab !

Vesiclemia - ANR 2022

Research Highlights

Sans titre.tif

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

Kerherve M, Rosinska S, Trillet K, Zeinaty A, Feyeux M, Nedellec S, Gavard J.

Front Cell Dev Biol 2022

 

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..

Sans titre 2.tif

Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma.

Andre-Grégoire G, Maghe C, Douanne T, Rosinska S, Spinelli F, Thys A, Trillet K, Jacobs KA, Ballu C, Dupont A, Lyne AM, Cavalli FMG, Busnelli I? Hyenne V, Goetz JG, Bidère N, Gavard J.

IScience 2022

 

Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression, as Glioblastoma Stem-like Cells (GSCs) releases pro-oncogenic, pro-angiogenic, and pro-inflammatory EVs. However, the molecular basis of EV release remains poorly understood. Here, we report the identification of the pseudokinase MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of EVs in GSCs. We find that genetic, protein, and pharmacological targeting of MLKL alters intracellular trafficking and EV release, and reduces GSC expansion. Nevertheless, this function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL reduces the tumor burden and the level of plasmatic EVs. This work highlights the necroptosis-independent role of MLKL in vesicle release and suggests that interfering with EV is a promising therapeutic option to sensitize glioblastoma cells.

Funding

Agence Nationale pour la Recherche
Canceropole GO

Fondation ARC
Fondation de France
Institut National du Cancer
Ligue contre le Cancer
Region Pays-de-la-Loire



 

logo.png
lossy-page1-1200px-LALIGUE_LOGO_C_RVB_V.
anr-logo-2021-complet.jpg
Fondation_ARC_Logo.jpg
img_1369294597732.jpg
inca-345x190_7.jpg
Logo-Pays-de-la-Loire-L.jpg