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

Gwennan André-Grégoire; Clément Maghe; Tiphaine Douanne; Sara Rosińska; Fiorella Spinelli; An Thys; Kilian Trillet; Kathryn A Jacobs; Cyndie Ballu; Aurélien Dupont; Anne-Marie Lyne; Florence M G Cavalli; Ignacio Busnelli; Vincent Hyenne; Jacky G Goetz; Nicolas Bidère; Julie Gavard

doi:10.1016/j.isci.2022.105118

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

iScience. 2022 Sep 13;25(10):105118. doi: 10.1016/j.isci.2022.105118. eCollection 2022 Oct 21.

Authors

Gwennan André-Grégoire^{1

2

3}, Clément Maghe^{1

3}, Tiphaine Douanne^{1

3}, Sara Rosińska^{1

3}, Fiorella Spinelli^{1

3}, An Thys^{1

3}, Kilian Trillet^{1

3}, Kathryn A Jacobs^{1

3}, Cyndie Ballu^{1

3}, Aurélien Dupont⁴, Anne-Marie Lyne^{5

6

7}, Florence M G Cavalli^{5

6

7}, Ignacio Busnelli^{3

8}, Vincent Hyenne^{3

8

9}, Jacky G Goetz^{3

8

9}, Nicolas Bidère^{1

3}, Julie Gavard^{1

2

3}

Affiliations

¹ Team SOAP, CRCI2NA, Nantes Université, Inserm, CNRS, Université d'Angers, Nantes, France.
² Institut de Cancérologie de l'Ouest (ICO), Saint-Herblain, France.
³ Equipe Labellisée Ligue Contre le Cancer, Paris, France.
⁴ SFR UMS CNRS 3480, INSERM 018, Biosit Biologie, Santé, Innovation Technologique, Rennes, France.
⁵ Institut Curie, PSL Research University, Paris, France.
⁶ Inserm, U900, Paris, France.
⁷ MINES ParisTech, CBIO - Centre for Computational Biology, PSL Research University, Paris, France.
⁸ INSERM UMR_S1109, Tumor Biomechanics, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
⁹ CNRS SNC5055, Strasbourg, France.

Abstract

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.

Keywords: Cancer; Cell biology; Functional aspects of cell biology.