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

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T1 - The Irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived transglutaminase 2

AU - Berg, Tracy J.

AU - Marques, Carolina

AU - Pantazopoulou, Vasiliki

AU - Johansson, Elinn

AU - Von Stedingk, Kristoffer

AU - Lindgren, David

AU - Jeannot, Pauline

AU - Pietras, Elin J.

AU - Bergström, Tobias

AU - Swartling, Fredrik J.

AU - Governa, Valeria

AU - Bengzon, Johan

AU - Belting, Mattias

AU - Axelson, Håkan

AU - Squatrito, Massimo

AU - Pietras, Alexander

PY - 2021/4/1

Y1 - 2021/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85104849873&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-20-1785

DO - 10.1158/0008-5472.CAN-20-1785

M3 - Article

C2 - 33483373

AN - SCOPUS:85104849873

VL - 81

SP - 2101

EP - 2115

JO - Cancer Research

JF - Cancer Research

SN - 1538-7445

IS - 8

ER -