Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma

Abstract

In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1mut glioma, investigations focused on metabolic alterations involving lipidomics’ present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1mut glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1mut inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1mut activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDHmut cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1mut glioma cell lines specifically, while it had little effect on the IDHWT cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes

“…Interestingly, the results revealed that gliomas, which are higher malignancy neoplasms compared to meningiomas, contained higher amounts of ceramides and their derivates (i.e., HexCer), while meningiomas contained higher levels of SMs, PCs, PEs, and LPCs (Figure S3 and Table S3). These alterations did not align with previous reports on biochemical alterations in gliomas compared to healthy tissue [6,41,42]; thus, further studies, possibly including spatially resolved in vivo sampling of healthy and cancerous tissue, are required to investigate this discrepancy in greater depth. It must also emphasized that the above-described comparison was performed as a proof-of-concept to verify the proposed method's applicability for the differentiation of brain tumors, and that further in-depth biological interpretation and discussion of these results was not undertaken, as currently available clinical tools already enable the easy identification of these lesions [25].…”

IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

“…Besides, it was found that sphingomyelin and monounsaturated fatty acids are accumulated in these organelles in IDH1-mutant cells. Based on this finding, the same group recently demonstrated that boosting these pathways via the addition of N,N-dimethylsphingosine (NDMS) and sphingosine C17 induced an apoptotic response in IDH1-mutant glioma cells [61].…”

Untargeted Metabolomics and Polyamine Profiling in Serum before and after Surgery in Colorectal Cancer Patients

“…Ceramide is also an important factor in apoptosis with its mechanism having been studied in depth [15]. In addition, because of an in vitro experiment assessing glioma treatment confirmed that apoptosis occurred when sphingosine kinase was inhibited in IDH cells and when sphingosine-1-phosphate production was inhibited [16]. However, no studies have yet been performed examining the association between phytosphingosines and CRC; meanwhile, they have been shown to induce inhibition of epithelial mesenchymal transition-related protein expression in malignant breast cancer [17].…”