RT Journal Article
SR Electronic
T1 Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 582221
DO 10.1101/582221
A1 Kathryn A. Jacobs
A1 Gwennan André-Grégoire
A1 Clément Maghe
A1 Ying Li
A1 An Thys
A1 Elizabeth Harford-Wright
A1 Kilian Trillet
A1 Tiphaine Douanne
A1 Jean-Sébastien Frénel
A1 Nicolas Bidère
A1 Julie Gavard
YR 2019
UL http://biorxiv.org/content/early/2019/03/23/582221.abstract
AB 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 (MALT1), 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 MALT1 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 MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomal-mediated death, concomitantly with mTOR inactivation and dispersion from lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.