Polyunsaturated Fatty Acid-Enriched Lipid Fingerprint of Glioblastoma Proliferative Regions Is Differentially Regulated According to Glioblastoma Molecular Subtype

Abstract

Glioblastoma (GBM) represents one of the deadliest tumors owing to a lack of effective treatments. The adverse outcomes are worsened by high rates of treatment discontinuation, caused by the severe side effects of temozolomide (TMZ), the reference treatment. Therefore, understanding TMZ’s effects on GBM and healthy brain tissue could reveal new approaches to address chemotherapy side effects. In this context, we have previously demonstrated the membrane lipidome is highly cell type-specific and very sensitive to pathophysiological states. However, little remains known as to how membrane lipids participate in GBM onset and progression. Hence, we employed an ex vivo model to assess the impact of TMZ treatment on healthy and GBM lipidome, which was established through imaging mass spectrometry techniques. This approach revealed that bioactive lipid metabolic hubs (phosphatidylinositol and phosphatidylethanolamine plasmalogen species) were altered in healthy brain tissue treated with TMZ. To better understand these changes, we interrogated RNA expression and DNA methylation datasets of the Cancer Genome Atlas database. The results enabled GBM subtypes and patient survival to be linked with the expression of enzymes accounting for the observed lipidome, thus proving that exploring the lipid changes could reveal promising therapeutic approaches for GBM, and ways to ameliorate TMZ side effects.

Biosynthesis and Significance of Fatty Acids, Glycerophospholipids, and Triacylglycerol in the Processes of Glioblastoma Tumorigenesis

“…In glioblastoma tumors, the level of PS is similar to that in healthy brain tissue ( Table 9 ) [ 159 ]. However, there is more PS in glioblastoma cancer nonstem cells than in glioblastoma cancer stem cells [ 78 ].…”

“…The GEPIA database shows that the expression of PI4K, PIP5K, and PIKFYVE is not significantly associated with patient prognosis in glioblastoma [ 48 ]. The level of PI in glioblastoma tumors is higher than in healthy brain tissue [ 159 ]. Glioblastoma cancer nonstem cells have a higher level of PI than glioblastoma cancer stem cells [ 78 ].…”

Dysregulated lipid metabolism in TMZ-resistant glioblastoma: pathways, proteins, metabolites and therapeutic opportunities

“…As shown in Table 1, multiple lipid metabolites are associated with TMZ resistance in GBM. In particular, decreased levels of sphingomyelins [13,14], polyunsaturated fatty acids (PUFAs) [15][16][17], glutathione [18,19], and taurine [20,21] may contribute to TMZ resistance by impairing cell membrane functions and antioxidant homeostasis. Increased levels of phosphatidylcholines [22,23], phosphatidylethanolamines [16,23], and myo-inositol [24,25] may be related to altered membrane composition or signaling pathways in TMZ-resistant GBM.…”

Ferroptosis: A novel therapeutic strategy and mechanism of action in glioma

“…Glioma cells undergo marked metabolic reprogramming (such as the Warburg effect) and GBM cell membrane lipid species are highly cell-type specific, with lipid metabolism involved in the occurrence and progression of GBM ( 64 ). The reprogramming of lipid metabolism is affected by the efficiency of acetyl-CoA ( 65 ) and isocitrate dehydrogenase (IDH) ( 66 ).…”