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

Fiche publication

Date publication

octobre 2022

Journal

iScience

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GOETZ Jacky , Dr HYENNE Vincent

Tous les auteurs :
André-Grégoire G, Maghe C, Douanne T, Rosińska 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

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36185361

Résumé

Extracellular vesicles (EVs) are lipid-based nanosized particles that convey biological material from donor to recipient cells. EVs play key roles in glioblastoma progression because glioblastoma stem-like cells (GSCs) release 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. , 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 EVs is a promising therapeutic option to sensitize glioblastoma cells.