Biology subjects

Andre-Gregoire, G.

Publications and source records attributed to Andre-Gregoire, G..

7 recordsLinked to original sources

bioRxiv2026

Molecular glue degraders of CK1α remodel lysosomes and limit ferroptosis in glioblastoma stem-like cells

Glioblastoma stem-like cells (GSCs) are highly plastic tumor cells that drive initiation, progression and therapeutic resistance. Although lysosomal homeostasis has emerged as a critical determinant of GSC fitness, the molecular mechanisms regulating this compartment remain incompletely understood. Here, using complementary proteomic approaches, we identified a lysosomal signature associated with the kinase CK1 in THP1 monocytic cells. Biochemical analyses revealed that genetic or siRNA-mediated depletion of CK1 altered the overall abundance and maturation of late endosome-lysosome-associated proteins in both THP1 cells and two patient-derived GSCs. This lysosomal remodeling was associated with impaired tumorsphere formation capacity in GSCs. To further explore the therapeutic potential of targeting CK1, we employed selective molecular glue degraders (MGDs). Acute CK1 degradation efficiently recapitulated lysosomal remodeling and impaired tumorsphere formation in GSCs. While CK1-targeted MGDs did not sensitize GSCs to lysosomal membrane permeabilization induced by L-leucyl-L-leucine methyl ester (LLOMe), they protected from GPX4 inhibitor-induced ferroptosis. Together, these findings identify CK1 as a regulator of lysosomal fitness and ferroptotic sensitivity, suggesting a connection between CK1-dependent lysosome remodeling and associated cell death pathways.

cancer biology↗

bioRxiv2025

The Kinase CK1α coordinates Initiation and Termination of the cGAS-STING Pathway

The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using proteomic approaches, we report that Casein Kinase 1 alpha (CK1) operates as a bimodal regulator of the cGAS-STING pathway. CK1 supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1 facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1 with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development. TEASERThis study unveils CK1 as a bimodal regulator of the cGAS-STING pathway.

immunology↗

bioRxiv2022

BCL-xL antagonizes the deleterious effects of KRAS on mitochondrial scaffolding

In addition to its canonical role as a regulator of mitochondrial outer membrane permeabilization, BCL-xL exerts diverse non canonical functions contributing to cancer cell aggressiveness. In particular it regulates KRAS intracellular activation levels. We herein explored the mechanistic basis for this effect by a spatially restricted biotin-labelling proteomic approach designed to characterize proteins whose proximity to KRAS, used as a bait, is BCL-xL dependant. BCL-xL loss relocalizes KRAS to the vicinity of mitochondrial proteins. Proximal proteins include the mitochondrial scaffold prohibitin 2 (PHB2), which also interacts with BCL-xL and the downregulation of which prevents BCL-xL sensitive effects of KRAS induced contacts between mitochondria and endosomes, and mitochondrial mass decrease. These results argue that BCL-xL prevents a negative feedback regulation of KRAS canonical signaling by KRAS interference with mitochondrial quality control.

cell biology↗

bioRxiv2021

The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.

cancer biology↗

bioRxiv2021

The Necroptosis Effector MLKL drives Small Extracellular Vesicle Release and Tumour Growth in Glioblastoma

Extracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.

cell biology↗

bioRxiv2019

Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

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-{kappa}B 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.

cell biology↗

bioRxiv2019

Pannexin-1 Channels govern the Generation of Necroptotic small Extracellular Vesicles

The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) controls the execution of necroptosis, a regulated form of necrosis that occurs in apoptosis-deficient conditions. Active oligomerized MLKL triggers the exposure of phosphatidylserine residues on the cell surface and disrupts the plasma membrane integrity by forming lytic pores. MLKL also governs the biogenesis and shedding of proinflammatory small extracellular vesicles (EVs) during the early steps of necroptosis, however the molecular basis is unknown. Here, we find that MLKL oligomers activate plasma membrane Pannexin-1 (PANX1) channels, concomitantly to the loss of phosphatidylserine asymmetry. This plasma membrane "leakiness" requires the Rab GTPase Rab27 isoforms, which usher the small EVs to their release. Conversely, PANX1 knockdown disorganized the small EVs machinery and precludes vesicles extrusion. These data identify a novel signaling nexus between MLKL, Rab27, and PANX1, and propose ways to interfere with small EV generation.

cell biology↗