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Targeting glioma-initiating cells via the tyrosine metabolic pathway
Daisuke Yamashita1, Joshua D Bernstock2, Galal Elsayed1
1Departments of1Neurosurgery and.
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 glioma-initiating 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.
Insights
Glioblastoma (GBM) tumor core cells exhibit distinct metabolic profiles from edge cells. Targeting tyrosine metabolism, specifically the tyrosine aminotransferase (TAT) enzyme, offers a promising therapeutic strategy for glioblastoma.
Area of Science:
- Neuro-oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glioblastoma (GBM) presents a poor prognosis due to significant tumor heterogeneity.
- Understanding metabolic differences within GBM tumors is crucial for developing effective treatments.
Purpose of the Study:
- To identify metabolic disparities between GBM tumor core and edge cells.
- To uncover novel therapeutic targets within GBM tumor metabolism.
Main Methods:
- Metabolic analyses were conducted on high-grade glioma (HGG) tissues and glioma-initiating cell (GIC) models.
- Data were integrated with the Ivy GBM dataset.
- Protein-level changes were confirmed using immunohistochemistry.
Main Results:
- Metabolic heterogeneity was observed in HGG tissues and GIC models.
- Tyrosine metabolism emerged as a potential therapeutic target, particularly in the GBM tumor core.
- Activation of tyrosine aminotransferase (TAT) in the tyrosine metabolic pathway correlated with therapeutic resistance in GBM core cells.
Conclusions:
- Selective inhibition of the tyrosine metabolism pathway shows potential as an adjuvant therapy for GBM.
- Targeting TAT may overcome therapeutic resistance in glioblastoma.
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