Targeting glioma-initiating cells via the tyrosine metabolic pathway

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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.

ABBREVIATIONS CL = classical; GBM = glioblastoma; GIC = glioma-initiating cell; HGG = high-grade glioma; IDH = isocitrate dehydrogenase; IHC = immunohistochemistry; Ivy GAP = Ivy Glioblastoma Atlas Project; MES = mesenchymal; PCA = principal component analysis; PN = proneural.
Article Information

Contributor Notes

Correspondence Ichiro Nakano: University of Alabama at Birmingham, AL. inakano@uabmc.edu.INCLUDE WHEN CITING Published online February 14, 2020; DOI: 10.3171/2019.11.JNS192028.

D.Y. and J.D.B. contributed equally to this work.

Disclosures Dr. Bernstock has positions and equity in CITC Ltd. and Avidea Technologies and is a member of the Scientific Advisory Board for POCKiT Diagnostics.
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