Masafumi Miyai1,2, Tomohiro Kanayama1, Fuminori Hyodo3, Takamasa Kinoshita1,2, Takuma Ishihara4, Hideshi Okada5, Hiroki Suzuki1, Shigeo Takashima6, Zhiliang Wu7, Yuichiro Hatano1, Yusuke Egashira2, Yukiko Enomoto2, Noriyuki Nakayama2, Akio Soeda2, Hirohito Yano2, Akihiro Hirata8, Masayuki Niwa9, Shigeyuki Sugie10, Takashi Mori11,12, Yoichi Maekawa7,13, Toru Iwama2, Masayuki Matsuo3, Akira Hara1, Hiroyuki Tomita1. 1. Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan. 2. Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan. 3. Department of Radiology, Gifu University Graduate School of Medicine, Gifu, Japan. 4. Gifu University Hospital, Innovative and Clinical Research Promotion Center, Gifu University, Gifu, Japan. 5. Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan. 6. Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan. 7. Department of Parasitology and Infectious Diseases, Gifu University Graduate School of Medicine, Gifu, Japan. 8. Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu, Japan. 9. Medical Science Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu, Japan. 10. Department of Pathology, Asahi University Hospital, Gifu, Japan. 11. Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan. 12. Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University (G-CHAIN), Gifu, Japan. 13. Domain of Integrated Life Systems, Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan.
Abstract
BACKGROUND: Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. METHODS: We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. RESULTS: Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. CONCLUSIONS: Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
BACKGROUND: Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. METHODS: We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. RESULTS: Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. CONCLUSIONS: Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
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