The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2
- 22 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (8), 2101-2115
- https://doi.org/10.1158/0008-5472.can-20-1785
Abstract
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 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. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) were 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.Other Versions
Funding Information
- Ollie & Elof Ericssons Foundation (n/a)
- Gösta Miltons Donationsfond (n/a)
- Stiftelsen Cancera (n/a)
- Viveca Jeppson (n/a)
- Maj-Britt and Allan Johansson (n/a)
- Seve Ballesteros Foundation (n/a)
- Cancerfonden (CAN 2016/328)
- Cancerfonden (CAN 2017/975)
- Cancerfonden (19 0283 Pj)
- Vetenskapsrådet (2014-02406)
- Vetenskapsrådet (2018-02864)
- Ragnar Söderbergs stiftelse (M20_16)
- Barncancerfonden (TJ2014-0016)
- Barncancerfonden (PR2014-0157)
- Barncancerfonden (PR2017-0040)
- Jeanssons Stiftelser (n/a)
- Crafoordska Stiftelsen (n/a)
- Region Skåne (n/a)
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