American Association for Cancer Research
00085472can201785-sup-244163_3_supp_6814449_qm5czr.pdf (1.39 MB)

Supplementary Figures from The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2

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journal contribution
posted on 2023-03-31, 04:46 authored by Tracy J. Berg, Carolina Marques, Vasiliki Pantazopoulou, Elinn Johansson, Kristoffer von Stedingk, David Lindgren, Pauline Jeannot, Elin J. Pietras, Tobias Bergström, Fredrik J. Swartling, Valeria Governa, Johan Bengzon, Mattias Belting, Håkan Axelson, Massimo Squatrito, Alexander Pietras

Supplementary Figures 1-6



The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured 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. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels 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. These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.

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