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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Spanish National Cancer Research Center (CNIO)
  • Academic Medical Center
  • University of Copenhagen
  • Uppsala universitet
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)2101-2115
Antal sidor15
TidskriftCancer Research
Volym81
Utgåva nummer8
StatusPublished - 2021 apr 1
PublikationskategoriForskning
Peer review utfördJa