Targeting glioma-initiating cells via the tyrosine metabolic pathway

Daisuke Yamashita, Joshua D. Bernstock, Galal Elsayed, Hirokazu Sadahiro, Ahmed Mohyeldin, Gustavo Chagoya, Adeel Ilyas, James Mooney, Dagoberto Estevez-Ordonez, Shinobu Yamaguchi, Victoria L. Flanary, James R. Hackney, Krishna P. Bhat, Harley I. Kornblum, Nicola Zamboni, Sung Hak Kim, E. Antonio Chiocca, Ichiro Nakano

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)721-732
Number of pages12
JournalJournal of neurosurgery
Volume134
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Glioblastoma
  • Heterogeneity
  • High-grade glioma
  • Metabolism
  • Nitrogen metabolism
  • Oncology
  • Tyrosine aminotransferase

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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