The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2
The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2
Abstract The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance, and following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-na?ve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy by reducing stemness in glioma.
von Stedingk Kristoffer、Lindgren David、Pietras Elin J.、Marques Carolina、Pantazopoulou Vasiliki、Governa Valeria、Bengzon Johan、Squatrito Massimo、Pietras Alexander、Johansson Elinn、Axelson H?kan、Berg Tracy J.、Belting Mattias、Swartling Fredrik J.、Bergstr?m Tobias
Department of Pediatrics, Clinical Sciences Lund, Lund University||Department of Oncogenomics, M1-131 Academic Medical Center University of AmsterdamDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityBiotech Research and Innovation Centre, University of CopenhagenSeve Ballesteros Foundation Brain Tumor groupDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund UniversityDivision of Neurosurgery, Department of Clinical Sciences, Lund Stem Cell Center, Lund UniversitySeve Ballesteros Foundation Brain Tumor groupDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University||Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund UniversityDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University
肿瘤学神经病学、精神病学基础医学
von Stedingk Kristoffer,Lindgren David,Pietras Elin J.,Marques Carolina,Pantazopoulou Vasiliki,Governa Valeria,Bengzon Johan,Squatrito Massimo,Pietras Alexander,Johansson Elinn,Axelson H?kan,Berg Tracy J.,Belting Mattias,Swartling Fredrik J.,Bergstr?m Tobias.The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2[EB/OL].(2025-03-28)[2025-05-09].https://www.biorxiv.org/content/10.1101/2020.02.12.945329.点此复制
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