PT  - JOURNAL ARTICLE
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  - Håkan Axelson
AU  - Massimo Squatrito
AU  - Alexander Pietras
TI  - The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2
AID  - 10.1101/2020.02.12.945329
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.12.945329
4099  - http://biorxiv.org/content/early/2020/02/13/2020.02.12.945329.short
4100  - http://biorxiv.org/content/early/2020/02/13/2020.02.12.945329.full
AB  - The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance; however, little is known about how the microenvironment responds to radiation. 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 inhibitors abrogated glioma stemness induced by irradiated astrocytes. TGM2 inhibition reduced survival of glioma cells in in vitro and ex vivo tumor models. 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 in glioma.