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The Irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived transglutaminase 2

Berg, Tracy J. LU ; Marques, Carolina ; Pantazopoulou, Vasiliki LU orcid ; Johansson, Elinn LU ; Von Stedingk, Kristoffer LU ; Lindgren, David LU ; Jeannot, Pauline LU ; Pietras, Elin J. ; Bergström, Tobias and Swartling, Fredrik J. , et al. (2021) In Cancer Research 81(8). p.2101-2115
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 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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
81
issue
8
pages
15 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:33483373
  • scopus:85104849873
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-20-1785
language
English
LU publication?
yes
id
3f4b54b7-9e9d-44cb-8733-83f629c28320
date added to LUP
2021-05-17 11:12:23
date last changed
2024-06-15 11:15:33
@article{3f4b54b7-9e9d-44cb-8733-83f629c28320,
  abstract     = {{<p>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. </p>}},
  author       = {{Berg, Tracy J. and Marques, Carolina and Pantazopoulou, Vasiliki and Johansson, Elinn and Von Stedingk, Kristoffer and Lindgren, David and Jeannot, Pauline and Pietras, Elin J. and Bergström, Tobias and Swartling, Fredrik J. and Governa, Valeria and Bengzon, Johan and Belting, Mattias and Axelson, Håkan and Squatrito, Massimo and Pietras, Alexander}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{8}},
  pages        = {{2101--2115}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{The Irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived transglutaminase 2}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-20-1785}},
  doi          = {{10.1158/0008-5472.CAN-20-1785}},
  volume       = {{81}},
  year         = {{2021}},
}