TY - JOUR T1 - The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2 JF - bioRxiv DO - 10.1101/2020.02.12.945329 SP - 2020.02.12.945329 AU - Tracy J. Berg AU - Carolina Marques AU - Vasiliki Pantazopoulou AU - Elinn Johansson AU - Kristoffer von Stedingk AU - David Lindgren AU - Elin J. Pietras AU - Tobias Bergström AU - Fredrik J. Swartling AU - Valeria Governa AU - Johan Bengzon AU - Mattias Belting AU - Håkan Axelson AU - Massimo Squatrito AU - Alexander Pietras Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/05/05/2020.02.12.945329.abstract N2 - 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-naïve 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.Competing Interest StatementThe authors have declared no competing interest. ER -