Outlining The Metabolic Landscape In Glioblastoma Based On Metabolic Axial Analysis

Background:Metabolic remodeling of glioblastoma supports the growth,motility,proliferation,and transformation of tumor cells,which is an emerging direction in oncology research.However,most of the literatures in this field have focused on the supporting role of single metabolic pathways in tumor activities,such as glycolysis and lipid metabolism,ignoring the heterogeneity within tumor and the flexibility of metabolic transformation.It is important for us to understand the significance and the role of metabolic heterogeneity in glioblastoma and to further shed light on unique therapeutic directions to explore metabolic heterogeneity in glioblastoma.Methods:We first established the main metabolic pathways of glioblastoma by cluster analysis using single-cell RNA sequencing data of glioblastoma.Then the correlation between metabolic pattern and cell phenotype was analyzed by cell fraction calculation.The regulators of cell metabolic pattern were explored by single cell copy number variation analysis and transcriptional activity analysis.Next,we used tissuelevel multiomics data to verify the association between cell-level metabolism and tissue-level metabolism.Finally,we analyzed the metabolic changes of glioblastoma cell models in vitro.Results:We found six metabolic orientations in glioblastoma and verified their robustness.Further analysis showed that these six metabolic directions were closely related to the phenotype of GBM cells and distributed into two metabolic axes:synaptic related metabolism-energy axis and glycolysis-lipid metabolism axis.Cells with different metabolic axes showed different copy number variation and transcriptional regulation network.At the same time,we observed the effect of cell metabolic pattern transformation in the metabolic pattern at the tissue level and identified that cells with different metabolic patterns were located in different ecological niches of GBM tissues.Finally,we analyzed the metabolic characteristics of the commonly used in vitro culture models and discussed their application in different metabolic research directions.Conclusions:Our results demonstrate the complexity of metabolic activity and regulation in glioblastoma,with two axial metabolisms suggesting that not all tumor cells are dependent on energy-regulated processes.In addition to glucose and fatty acids,metabolic pathways involved other biomolecules such as glycan,cholesterol,phospholipid,and nicotinamide,which are also important for tumor cells with different ecological niches and phenotypes.Histological analysis suggests that the overall metabolic pattern of tumors is affected by the proportion of metabolically dependent tumor cells and immune cell infiltration.Finally,during in vitro cell experiments,cell lines should be carefully selected for studies on different metabolic directions,because metabolic patterns in different cell lines are distorted compared with those observed in GBM tissues.In conclusion,our study establishes a basic metabolic landscape of glioblastoma and provides new insights into the metabolic heterogeneity of glioblastoma.