Daisuke Yamashita1, Joshua D Bernstock2, Galal Elsayed1, Hirokazu Sadahiro1,3, Ahmed Mohyeldin4, Gustavo Chagoya1, Adeel Ilyas1, James Mooney1, Dagoberto Estevez-Ordonez1, Shinobu Yamaguchi1, Victoria L Flanary1, James R Hackney5, Krishna P Bhat6, Harley I Kornblum7,8,9, Nicola Zamboni10, Sung-Hak Kim1,11,12, E Antonio Chiocca2, Ichiro Nakano1,13. 1. Departments of1Neurosurgery and. 2. 2Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 3. 3Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. 4. 4Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio. 5. 5Pathology. 6. 6Department of Translational Molecular Pathology and Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7. 7Departments of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior. 8. 8Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior. 9. 13Broad Stem Cell Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California. 10. 9Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland. 11. 10Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju; and. 12. 11Gwangju Center, Korea Basic Science Institute, Gwangju, Republic of Korea. 13. 12O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Alabama.
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.
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 GBMtumor 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 GBMtumor 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.
Authors: Maheedhara R Guda; Kiran K Velpula; Swapna Asuthkar; Charlie P Cain; Andrew J Tsung Journal: Int J Mol Sci Date: 2020-05-07 Impact factor: 5.923
Authors: Elise P W Jenkins; Alina Finch; Magda Gerigk; Iasonas F Triantis; Colin Watts; George G Malliaras Journal: Adv Sci (Weinh) Date: 2021-07-22 Impact factor: 16.806