Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184451 | GEO | 2021/09/22
REPOSITORIES: GEO
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Project description:Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21-/- mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. SIGNIFICANCE: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.
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Project description:Healthy adult male C57BL/6 mice (8 weeks of age) were randomly divided into sham irradiation group (sham) and cranial ir-radiation group (5 Gy 4 d). For the 5 Gy 4 d group, the head of mice were received 20 Gy X-rays (RAD Source RS 2000 series, Suwanee, USA), applied as four doses of 5 Gy in consecutive 4 days at a dose rate of 2.33 Gy/ min. The rest of mouse’s body was completely protected by a 2-cm thick lead shield. For the sham group, the mice were maintained in the same procedure except X-ray irradiation. No radiation leakage through the shield occurred in the present study, as verified by dose measurement of testis under shielding and morphological structure of peripheral main organs. Meanwhile, Monte Carlo simulation was used to calculate the absorbed dose of the peripheral main organs when mice head was irradiated with 20 Gy X-rays. The results showed that the absorbed dose of testis under shielding was 0.018 Gy, which was only 0.9‰ of cranial absorbed dose. Tandem mass tag (TMT) quantitative proteomic analysis of testis at 4 W after cranial irradiation was carried out by LC-BIO Co., Ltd (Hangzhou, China). The differentially expressed proteins (DEPs) were screened and obtained using the cutoffs of fold change > 1.2 and P < 0.05. For bioinformatics analysis, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using the DAVID 6.8 database (https://david.ncifcrf.gov/).
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Project description:Our in vivo study measures miRNA and gene expression changes in human blood cells in response to ionizing radiation in order to develop miRNA signatures that can be used as biomarkers for radiation exposure. Blood was collected from 8 radiotherapy patients immediately prior to and at 4 h after total body irradiation with 1.25 Gy X-rays. Both miRNA and gene expression changes were measured by means of quantitative PCR and microarray hybridization, respectively. Patients were in complete remission at the time of blood collection. Out of 223 differentially expressed genes, 37 were both downregulated and predicted targets of the upregulated miRNAs. Both miRNA and gene control of biological processes such as hemopoiesis and the immune response is increased after irradiation, whereas metabolic processes are underrepresented among all differentially expressed genes and the genes controlled by miRNAs. Sixteen human whole-blood samples were included in this study. Eight samples were collected shortly before total body irradiation. The other 8 samples were collected at 4 h after total body irradiation with 1.25 Gy X-rays.
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Project description:The aim of this study was to analyze the host responses to ionizing radiation by nuclear factor-κB (NF-κB) bioluminescence imaging-guided transcriptomic tool. Transgenic mice, carrying the NF-κB-driven luciferase gene, were exposed to a single dose of 8.5 Gy total-body irradiation. In vivo imaging showed that a maximal NF-κB-dependent bioluminescent intensity was observed at 3 h after irradiation and ex vivo imaging showed that liver, intestine, and brain displayed strong NF-κB activations. Microarray analysis of these organs showed that irradiation altered gene expression signatures in an organ-specific manner. Pathway analysis showed that pathways associated with metabolism and immune system were altered primarily in liver and intestine. the upregulation of fatty acid binding protein 4, serum amyloid A2, and serum amyloid A3, which are participated in both inflammation and lipid metabolism, suggesting that irradiation might affect the cross pathways of metabolism and inflammation. Moreover, The upregulation of chemokine (CC-motif) ligand 5, chemokine (CC-motif) ligand 20, and Jagged 1 genes suggested that these genes might contribute to the radiation enteropathy. Male transgenic mice (6 to 8 weeks old) were exposed to a single dose of whole-body X-rays generated at 6 MV (Clinac® 21EX medical linear accelerator, Varian, Palo Alto, CA, USA) and at a dose rate of 4 Gy/min. Mice were imaged at 0 h, 1 h, 3 h, 9 h, 24 h, 48 h, or 72 h, or on 7 d or 14 d after irradiation with 8.5 Gy. RNAs were extracted at 3 h after irradiation.
2012-01-01 | E-GEOD-25208 | biostudies-arrayexpress
Project description:4plex_barley_2017_01 - transcriptomic assay on embryos after barley seeds gamma_irradiation - Why radiation exposure on seeds at low doses causes stimulation of plant growth after germination? - Barley dry seeds of variety “Nur” were irradiated by gamma-rays (Co-60) at doses 20 Gy (stimulatory) and 100 Gy (inhibitory). Immediately after irradiation we put seeds for germination to Petri dishes containing water filter paper; embryos were taken 2h after irradiation, embryos with embrionic roots were taken 24 and 48h after irradiation. The following comparisons have been made: non-irradiated (0 Gy), 2h vs. 20 Gy, 2h; 0 Gy, 24h vs. 20 Gy, 24h; 0 Gy, 48h vs. 20 Gy, 48h; 0 Gy, 24h vs. 100 Gy, 24h. Three independent biological replicates were used.
2019-12-01 | GSE117356 | GEO
Project description:Arabidopsis cmt3 mutant showed neither DNA hypomethylation nor transcriptional activation of silenced repeats by gamma rays, which was found in wild type (WT). We used microarrays to compare the global transcriptional changes between the WT and cmt3 after the irradiation of 200 Gy. Transcriptions of transposition-related genes seemed to be differently affected in the WT and cmt3 by gamma rays, depending on the epigenetic codes of the genome. However, genome-wide transcriptions of the WT and cmt3 couldn't be positively correlated with the different levels of DNA methylation after the irradiation of 200 Gy.
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Project description:Baseline gene expression of human lymphocytes 24 hours after 5 Gy gamma irradiation We used microarrays to detail the global gene expression of human lymphocytes after irradiation Compare the gloable gene expression of human lymphocyte 24 hours after exposure to doses between 0 and 5 Gy γ rays
2013-04-01 | E-GEOD-44245 | biostudies-arrayexpress
Project description:Hela cells were used to evaluate the protoporphytin IX (PpIX) effects on X-ray irradiation. Treatment conditions were (1) control group (untreated cells); (2) cells treated with 1 μg /ml PpIX for 6 hours; (3) cells irradiated with 3Gy X-rays; (4) cells treated with 1 μg /ml PpIX for 6 hours prior to irradiation with 3Gy X-rays. Hela cells gene expressions in 4 groups were measured at 24 hours after exposure to 0 and 3 Gy X-rays plus treatment with PpIX prior to irradiation.
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