Targeting glioma-initiating cells via the tyrosine metabolic pathway

OBJECTIVE Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 gliomainitiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies. OBJECTIVE Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 gliomainitiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to

Automated summary

Despite aggressive multimodal therapy, glioblastoma (GBM) still has a poor prognosis due to tumor heterogeneity at the molecular and cellular levels. This study aimed to identify metabolic differences between GBM tumor core cells and edge cells, potentially revealing new therapeutic targets related to tumor metabolism. Comprehensive metabolic analyses on high-grade glioma tissues and glioma-initiating cell culture models showed metabolic heterogeneity, with implications for targeting tyrosine metabolism in GBM, especially in the tumor core region. Activation of the enzyme tyrosine aminotransferase (TAT) within this pathway influenced therapeutic resistance in the GBM core, suggesting selective inhibition of tyrosine metabolism as a promising adjuvant therapy for GBM.