Extracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.

中文翻译：

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坏死病效应器MLKL驱动胶质母细胞瘤中的小细胞外囊泡释放和肿瘤生长

细胞外囊泡（EVs）是基于脂质的纳米级颗粒，可将生物材料从供体传递到受体细胞。它们在肿瘤进展中起关键作用，特别是在胶质母细胞瘤中，其中胶质母细胞瘤干细胞样细胞（GSC）的亚群可能代表了肿瘤来源的电动汽车的重要来源。但是，对于GSC生产和发布EV的机制仍知之甚少。在这里，我们报告鉴定为KLSC，它是坏死性细胞死亡的关键死亡效应器，作为GSC小型EV组成型分泌的调节剂。通过遗传，蛋白质消耗或化学方法靶向MLKL可以改变内体运输和EV释放并减少体外GSC的扩增。归因于MLKL的此功能似乎独立于其在尸检中的作用。体内，MLKL的药理抑制作用既可以降低异种移植小鼠的肿瘤负担，又可以降低血浆电动汽车的水平。这项工作加强了MLKL在内体运输中非致命作用的想法，并暗示干扰EV生物发生是使胶质母细胞瘤细胞致死的一种有前途的治疗选择。