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Paracaspase MALT1 regulates glioma cell survival by controlling endo‐lysosome homeostasis
Author(s) -
Jacobs Kathryn A,
AndréGrégoire Gwennan,
Maghe Clément,
Thys An,
Li Ying,
HarfordWright Elizabeth,
Trillet Kilian,
Douanne Tiphaine,
Alves Nicolau Carolina,
Frénel JeanSébastien,
Bidère Nicolas,
Gavard Julie
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102030
Subject(s) - library science , humanities , art , computer science
Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem‐like cells ( GSC ), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa‐associated lymphoid tissue l ( MALT 1), a protease previously linked to antigen receptor‐mediated NF ‐κB activation and B‐cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT 1 largely impaired the expansion of patient‐derived stem‐like cells in vitro , and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo . Blocking MALT 1 protease activity increases the endo‐lysosome abundance, impairs autophagic flux, and culminates in lysosomal‐mediated cell death, concomitantly with mTOR inactivation and dispersion from endo‐lysosomes. These findings place MALT 1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo‐lysosomes.