Studying the membrane asymmetry upon aggressiveness and invasiveness of glioblastoma cells in the context of mechanosensation
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- Although significant progress has been made in unravelling cancer genetics, the biophysical and compositional alterations of cancer cell plasma membranes remain relatively underexplored, particularly in the context of mechanosensation and tissue invasion. Glioblastoma multiforme (GBM), the most common and aggressive brain cancer, is known for its invasiveness and very high resistance to treatment. Emerging evidence suggests that GBM cells exhibit disruptions in lipid metabolism, which may lead to altered biophysical and mechanical cell membrane properties and hence altered mechanosensation that might favour cell migration and tissue invasion. To investigate the relationship between membrane alterations and GBM invasiveness, we employed Giant Plasma Membrane Vesicles (GPMVs) and whole GBM cells (U87 and U251) as model systems that were either produced in static or migrating conditions. GPMVs offer unique advantages for studying membrane properties as they contain only lipids and proteins from the plasma membrane and will hence be used to determine its lipid composition and biophysical membrane properties. We optimized GPMV production to enable lipidomic analysis via liquid chromatography-mass spectrometry (LC-MS), focusing on the lipid composition of both the inner and outer leaflets of the plasma membrane (PM). Additionally, we compared the packing of the PM in GPMVs and GBM cells using imaging flow cytometry. Finally, we assessed the expression levels of key genes involved in membrane composition and asymmetry—TMEM16F (lipid scrambling), SMPD1 (sphingomyelin metabolism), and GRAMD1B (cholesterol metabolism). The results showed that U251 exhibits increased expression of TMEM16F and GRAMD1b during migration. Additionally, U251 demonstrated decreased membrane packing during migration, indicating a potential alteration in PM composition that could affect mechanical properties. U87 showed no difference in packing or expression of TMEM16F, SMPD1 and GRAMD1b during migration. However, U87 expressed more GRAMD1b than U251, highlighting high transcriptomic heterogeneity between GBM cell lines. Altogether, it was shown that U251 GBM cells alter their lipid metabolism and membrane properties during migration while this was less clear for U87 cells. To confirm these results, we await the lipidomics analysis and we would like to correlate these results to real mechanical membrane properties in these cells. This could finally allow us to selectively modulate these membrane properties in a way that suppresses migration and invasiveness.