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

Research output: Contribution to journalArticle

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 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.

Details

Authors
Organisations
External organisations
  • Spanish National Cancer Research Center (CNIO)
  • Academic Medical Center of University of Amsterdam (AMC)
  • University of Copenhagen
  • Uppsala University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)2101-2115
Number of pages15
JournalCancer Research
Volume81
Issue number8
Publication statusPublished - 2021 Apr 1
Publication categoryResearch
Peer-reviewedYes