Biology subjects

Laiakis, E. C.

Publications and source records attributed to Laiakis, E. C..

2 recordsLinked to original sources

bioRxiv2022

Radiation therapy promotes unsaturated fatty acids to maintain survival of glioblastoma

PurposeRadiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. MethodsWe analyzed in vitro extracellular flux and profiled targeted metabolites as well as free fatty acids in two syngenic models of glioblastomas 24hrs post RT. Metabolic adaptation of irradiated GBM were confirmed in vivo by mass spectrometry imaging. The role of the fatty acid synthase (FASN) in RT-induced lipid metabolites was assessed by genetical and pharmacological inhibition of Fasn in irradiated GBM cells. The impact of FASN-mediated lipids on endoplasmic reticulum (ER) stress and apoptosis of irradiated GBM cells were performed by transmission electronic microscopy, western blot, clonogenic assay and flow cytometry. Inhibition of FASN combined with focal RT was assessed in mice. Analysis of a public dataset of GBM patients was performed to correlate preclinical findings. ResultsHere, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increase formation of lipid droplets to prevent ER stress. We uncovered that FASN is critical for lipid accumulation of irradiated GBM and demonstrate that genetic suppression and pharmacological inhibition of FASN lead to mitochondrial dysfunction and apoptosis. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. ConclusionsOverall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.

cell biology↗

bioRxiv2019

Temporal Effects on Radiation Responses in Nonhuman Primates: Identification of Biofluid Small Molecule Signatures by Gas Chromatography - Mass Spectrometry Metabolomics

Whole body exposure to ionizing radiation (IR) (> 0.7 Gy) damages tissues leading to a range of physical symptoms contributing to acute radiation syndrome (ARS). Radiation biodosimetry aims to determine characteristic early biomarkers indicative of radiation exposure (generally at doses > 2 Gy) and is a necessity for effective triage in the event of an unanticipated radiological incident and emergency preparedness. Radiation metabolomics can address this aim by assessing metabolic perturbations following various emergency scenarios (e.g., elapsed time to medical care, absorbed dose, combined injury). Gas chromatography - mass spectrometry (GC-MS) is a standardized platform ideal for chromatographic separation, identification, and quantification of metabolites to discriminate molecular signatures that can be utilized in assessing radiation injury. We performed GC time-of-flight (TOF) MS for global profiling of nonhuman primate (NHP) urine and serum samples up to 60 d after a single 4 Gy {gamma}-ray total body exposure. Multivariate statistical analysis showed a higher separation of groups from urine signatures vs. serum signatures. We identified biofluid markers involved in amino acid, lipid, purine, and serotonin metabolism, some of which may indicate host microbiome dysbiosis. Sex differences were observed amino acid fold changes in serum samples. Additionally, we explored mitochondrial dysfunction by analysis of tricarboxylic acid (TCA) intermediates with a GC tandem quadrupole (TQ) MS platform in samples collected in a time course during the first week (1, 3, 5, and 7 d) after exposure. By adding this temporal component to our previous work exploring dose effects at a single time point of 7 d, we observed the highest fold changes occurring at 3 d, returning closer to basal levels by 7 d. These results emphasize the utility of both MS-based metabolomics for biodosimetry and complementary analytical platforms for increased metabolome coverage.

biochemistry↗