Mojgan DJAVAHERI-MERGNY: "Targeting intracellular cholesterol transport for inducing lysosomal damage and immunogenic cell death in cancer" - Salle Délégation INSERM

Mojgan DJAVAHERI-MERGNY, CRHC INSERM, Centre de recherche des Cordeliers Paris, France
Domaine d'expertise : les liens moléculaires entre les altérations des fonctions des lysosomes et de l'autophagige et leurs conséquences sur l'induction d'une mort cellulaire programmée, la différenciation cellulaire et l'oncogenèse
26 septembre 2025 à 10h30, dans la salle verte du batiment D des locaux de l'IRSD / Infinity (délégation régionale Inserm) et retransmission TEAMS

ABSTRACT
Lysosomes serve as an intracellular platform that coordinates anabolic and catabolic processes, cell signaling, and transcriptional programs. These organelles allow the adaptation of cancer cells to a changing microenvironment by supplying them with essential metabolites and energy for their survival and proliferation. A major player in the lysosomal adaptive response is the transcription factor EB (TFEB), which is part of the microphthalmia/transcription factor E (MIT/TFE) family of transcription factors (1). TFEB plays a pivotal role in driving the expression of several genes associated with lysosome function and biogenesis, including those participating in autophagy. While TFEB and autophagy function as adaptive mechanisms to reestablish cellular homeostasis in response to stressors, TFEB- induced lysosomal biogenesis and enlargement can render cancer cells more vulnerable to compounds targeting lysosomes. This vulnerability opens the door for developing new strategies to combat cancer by simultaneously targeting the lysosome and activating TFEB.
Through screening 1,200 drugs that have been approved by the Food and Drug Administration (FDA), we identified two antidepressants, sertraline and indatraline that efficiently triggered TFEB activation (2). Both compounds exhibited significant cytotoxicity properties and induced lysosomal membrane permeabilization in various cancer cell lines. In a mice sarcoma model, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to protect against tumor growth in mice. In a therapeutic setting, a single dose of each compound was enough to significantly impair the outgrowth of established tumors in a T cell-dependent manner. At the molecular level, we demonstrated that both sertraline and indatraline acted as inhibitors of cholesterol trafficking in the cell. Altogether, these finding support the repositioning of sertraline and indatraline for the treatment of sarcomas and encourage the extension of this study to other compounds that inhibit cholesterol transport