Metabolism and signaling crosstalk in glioblastoma progression and therapy resistance

Abstract

Glioblastoma is the most common form of primary malignant brain tumor in adults and one of the most lethal human cancers, with high recurrence and therapy resistance. Glioblastoma cells display extensive genetic and cellular heterogeneity, which precludes a unique and common therapeutic approach. The standard of care in glioblastoma patients includes surgery followed by radiotherapy plus concomitant temozolomide. As in many other cancers, cell signaling is deeply affected due to mutations or alterations in the so‐called molecular drivers. Moreover, glioblastoma cells undergo metabolic adaptations to meet the new demands in terms of energy and building blocks, with an increasing amount of evidence connecting metabolic transformation and cell signaling deregulation in this type of aggressive brain tumor. In this review, we summarize some of the most common alterations both in cell signaling and metabolism in glioblastoma, presenting an integrative discussion about how they contribute to therapy resistance. Furthermore, this review aims at providing a comprehensive overview of the state‐of‐the‐art of therapeutic approaches and clinical trials exploiting signaling and metabolism in glioblastoma.

Application of the HILIC-MS Novel Protocol to Study the Metabolic Heterogeneity of Glioblastoma Cells

“…Metabolomics, the study of small molecule metabolites in biological systems, has emerged as a powerful tool for understanding the metabolic alterations in glioblastoma cells and identifying potential therapeutic targets. Studies in metabolomics, including those focusing on glioblastoma, have identified several altered or dysregulated metabolic pathways in comparison to healthy cells [3][4][5][6][7][8]. Examples of these alterations include changes in glucose and amino acid metabolism.…”

“…Glioblastoma cells have been shown to rely on glucose and several amino acids to support their high energy demands [9][10][11][12][13][14], as well as to utilize their carbon skeletons for anabolic processes such as lipid [15,16] and nucleotide synthesis [17]. Despite the genetic and cellular heterogeneity observed in glioblastoma cells within tumor [4], as well as heterogeneity in their metabolism [18][19][20], targeting metabolic pathways has emerged as a promising therapeutic strategy. Therefore, further studies focusing on and revealing the metabolic aspects of cancer cells could provide the valuable knowledge.…”

Application of the Hydrophilic Interaction Liquid Chromatography (HILIC-MS) Novel Protocol to Study the Metabolic Heterogeneity of Glioblastoma Cells

“…Metabolomics, the study of small molecule metabolites in biological systems, has emerged as a powerful tool for understanding the metabolic alterations in glioblastoma cells and identifying potential therapeutic targets. Studies in metabolomics, including those focusing on glioblastoma, have identified several altered or dysregulated metabolic pathways in comparison to healthy cells [ 3 , 4 , 5 , 6 , 7 , 8 ]. Examples of these alterations include changes in glucose and amino acid metabolism.…”

“…Glioblastoma cells have been shown to rely on glucose and several amino acids to support their high energy demands [ 9 , 10 , 11 , 12 , 13 , 14 ], as well as to utilize their carbon skeletons for anabolic processes such as lipid [ 15 , 16 ] and nucleotide synthesis [ 17 ]. Despite the genetic and cellular heterogeneity observed in glioblastoma cells within tumors [ 4 ], as well as heterogeneity in their metabolism [ 18 , 19 , 20 ], targeting metabolic pathways has emerged as a promising therapeutic strategy. Therefore, further studies focusing on and revealing the metabolic aspects of cancer cells could provide valuable knowledge.…”