Société Française de Biochimie et Biologie Moléculaire

Kathryn Jacobs - MARCH 2020

Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis EMBO J. 39, e102030 Jacobs, K.A., André-Grégoire, G., Maghe, C., Thys, A., Li, Y., Harford-Wright, E., Trillet, K., Douanne, T., Alves Nicolau, C., Frénel, J.-S., et al. (2020).


Kathryn Jacobs, 27 years old, received her bachelor’s degree in Biochemistry from Washington University in Saint Louis, in Saint Louis, Missouri, USA. She then obtained a Masters degree in molecular biology from Pierre and Marie Curie University (UPMC) in Paris France. Currently, she is a PhD student in the Signaling in Oncogenesis, Angiogenesis, and Permeability (SOAP) Laboratory at the Centre de Recherche en Cancerologie, Immunologie Nantes Angers (CRCINA), under the direction of Dr. Julie Gavard. Her work focuses on analyzing the role of Non- oncogene addiction in the maintenance of Glioblastoma stem like cells (GSCs), in order to identify potential therapeutic targets. Through analysis of The Cancer Genome Atlas for NF-kB pathway expression in Glioblastoma (GBM), we unveiled that the paracaspase MALT1 is correlated with poor prognosis in GBM. Moreover, knockdown or pharmacological blockade of this protease was lethal in GSCs. Notably, MALT1 inhibition increases the endo-lysosomal compartment and reduces mTOR activation. This work lead to the publication “Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis. » as the cover article in the EMBO Journal in January 2020.



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Summury Article

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 stemlike 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 mucosaassociated lymphoid tissue l (MALT1), a protease previously linked to antigen receptormediated NFκB activation and Bcell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patientderived stemlike cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endolysosome abundance, impairs autophagic flux, and culminates in lysosomalmediated cell death, concomitantly with mTOR inactivation and dispersion from endolysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endolysosomes.