2024-01-29 09:52:33
Glioblastoma is the most common and deadliest cancer of the central nervous system in adults. Despite a standard treatment protocol established in 2005, combining maximum surgery followed by radio- and chemotherapy sessions, patients survive on average only 15 months following their diagnosis. This aggressiveness is notably linked to the presence of cancer stem cells called glioblastoma stem-like cells, or GSCs. These cells, involved in the initiation, growth, and relapse of the tumor, therefore represent preferential targets for the development of new therapeutic strategies.
Lysosomes play a critical role in maintaining cancer stem cells
Lysosomes, the constituent elements of the cell, form a dynamic network of vesicles (a sort of small bags), with an acidic pH, involved in the movement of substances inside the cell. They participate in metabolic processes, and are responsible for the digestion of particles ingested by the cell and the degradation of defective cellular components.
Previous work shows that they also enable the survival of glioblastoma stem cells outside their protective niche within the tumor. Indeed, lysosomes extend growth factor signals and facilitate the diffusion and proliferation of cancer cells. In glioblastoma stem cells, altering the quantity and quality of lysosomes leads to specific death of these cells. Lysosomes are thus a critical therapeutic target to influence the life-and-death decisions of these glioblastoma stem cells and thus control their population.
To destabilize the wall of the small bags that are the lysosomes, at the heart of glioblastoma stem cells, scientists have identified the role of the MALT1 protease (from the paracaspase family). Inhibiting this enzyme, recently defined as a crucial mediator of lysosome homeostasis, results in lysosome-dependent death of glioblastoma stem cells. This, via a mechanism involving the mRNA binding protein Quaking and the modulation of the expression of key proteins of the lysosomal compartment. However, the mechanisms of action of MALT1 remain poorly characterized.
A flood of lysosomal cholesterol to destroy glioblastoma stem cells
Today, the results of this study provide a better understanding of the workings of the system. Indeed, they suggest that the repression of MALT1, by pharmacological agents or by RNA interference (a technique which makes it possible to specifically inhibit the synthesis of the protein by destroying the messenger which corresponds to it), modifies homeostasis (l balance between the inside and the outside) of cholesterol. Cholesterol then accumulates in vesicles in the lysosome compartment and late endosomes. This failure in cholesterol supply results in cell death and defects in autophagy (the cell’s self-cleaning system), which can be partially reversed by providing glioblastoma stem cells with blood-permeable cholesterol. membrane. These results were obtained through the combination of RNA sequencing analysis (RNA-seq) and proteome quantification, carried out on patient-derived glioblastoma stem cells subjected to a pharmacological inhibitor of the proteolytic activity of MALT1.
From a molecular perspective, targeted analysis of the lysosome proteome revealed that Niemann-Pick C (NPC)-type lysosomal cholesterol transporters are less present when MALT1 activity is hampered. Consistent with these data, pharmacologically blocking or silencing the expression of these NPC1/2 transporters reproduces the effects of MALT1 loss-of-function, suggesting a similar action of these two molecules. Finally, inhibition of MALT1 or NPC1/2 slows tumor growth in immunocompromised mouse models carrying patient-derived glioblastoma stem cells.
This work therefore allowed the mapping of events at the subcellular level, participating in lysosomal destabilization induced by the molecular and pharmacological targeting of the MALT1 paracaspase. These data raise the idea that the properties and maintenance of glioblastoma stem cells rely on lysosomal cholesterol homeostasis.
© Clément Maghe
Figure: Model of MALT1 action in maintaining lysosomal homeostasis
The MALT1 protease modulates the lysosomal localization of NPC1 protein and cholesterol homeostasis. In glioblastoma stem-like cells (GSCs), inhibiting the activity of the paracaspase MALT1 or interfering with its expression level remodels the lysosomal compartment, notably by reducing the amount of the cholesterol transporter NPC1. This is followed by intra-lysosomal retention of cholesterol, inducing a defect in autophagic degradation, activation of the machinery allowing the import and synthesis of cholesterol, and finally, cell death of GSCs. Adding exogenous cholesterol to GSCs whose MALT1 activity has been inhibited partially counteracts the phenotypes mentioned above, thus placing lysosomal transport of cholesterol as a target of GSCs.
Learn more:
The paracaspase MALT1 controls cholesterol homeostasis in glioblastoma stem-like cells through lysosome proteome shaping. Maghe C, Trillet K, André-Grégoire G, Kerhervé M, Merlet L, Jacobs KA, Schauer K, Bidère N, Gavard J. Cell Rep. 2024 Jan 5;43(1):113631. doi: 10.1016/j.celrep.2023.113631.
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