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

被引：6

作者：

Andre-Gregoire, Gwennan ^{[1
,2
,3
]}

Maghe, Clement ^{[1
,3
]}

Douanne, Tiphaine ^{[1
,3
]}

Rosinska, Sara ^{[1
,3
]}

Spinelli, Fiorella ^{[1
,3
]}

Thys, An ^{[1
,3
]}

Trillet, Kilian ^{[1
,3
]}

Jacobs, Kathryn A. ^{[1
,3
]}

Ballu, Cyndie ^{[1
,3
]}

Dupont, Aurelien ^{[4
]}

Lyne, Anne-Marie ^{[5
,6
,7
]}

Cavalli, Florence M. G. ^{[5
,6
,7
]}

Busnelli, Ignacio ^{[3
,8
]}

Hyenne, Vincent ^{[3
,8
,9
]}

Goetz, Jacky G. ^{[3
,8
,9
]}

Bidere, Nicolas ^{[1
,3
]}

Gavard, Julie ^{[1
,2
,3
]}

机构：

[1] Univ Angers, Nantes Univ, CNRS, INSERM,Team SOAP,CRCI2NA, Nantes, France

[2] Inst Cancerol Ouest ICO, Saint Herblain, France

[3] Equipe Labellisee Ligue Canc, Paris, France

[4] Biosit Biol Sante Innovat Technol, INSERM 018, SFR UMS CNRS 3480, Rennes, France

[5] PSL Res Univ, Inst Curie, Paris, France

[6] INSERM, U900, Paris, France

[7] PSL Res Univ, CBIO Ctr Computat Biol, Mines ParisTech, Paris, France

[8] Univ Strasbourg, Federat Med Translat Strasbourg FMTS, Tumor Biomech, INSERM UMR S1109, Strasbourg, France

[9] CNRS SNC5055, Strasbourg, France

来源：

ISCIENCE | 2022年 / 25卷 / 10期

关键词：

MIXED LINEAGE KINASE; MEDIATES NECROPTOSIS; PROGRAMMED NECROSIS; DOMAIN-LIKE; STEM-CELLS; DOWNSTREAM; PROMOTE; MICROENVIRONMENT; TEMOZOLOMIDE; TRAFFICKING;

D O I：

10.1016/j.isci.2022.105118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. 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 EVs is a promising therapeutic option to sensitize glioblastoma cells.

引用

页数：27

共 75 条

[1] Intercellular transfer of the oncogenic receptor EGFrvIII by microvesicles derived from tumour cells [J].