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.
| S-EPMC9724593 | biostudies-literature
Project description:Elimination of radiation-induced senescence in the brain tumor microenvironment attenuates glioblastoma recurrence
| PRJNA764698 | ENA
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/).
2022-10-14 | PXD037407 |
Project description:Significant impacts on gene expression were observed generations after exposure in ionising radiation exposed nematodes. C. elegans were exposed to 1 Gy of X-rays and their gene expression was analysed several generations later with whole genome oligoarrays (Washington University).
2011-07-31 | E-GEOD-29979 | biostudies-arrayexpress
Project description:Radiation lung injury is characterized by early inflammation and late fibrosis. The causes underlying the chronic, progressive nature of radiation injury are poorly understood. Here, we report that the gene expression of irradiated lung tissue correlates with that observed in the lungs in aged animals. We demonstrate that NOX4 expression and superoxide elaboration is increased in irradiated lungs and pneumocytes in a dose dependent fashion. We used microarrays to detail the global programme of gene expression and report that irradiated lung tissue correlates with that observed in the lungs in aged animals. Female C57Bl/Ncr mice, aged 10 weeks were treated with/ without radiation to the thorax with a X-RAD 320 x-ray irradiator at a dose rate of 2.61 Gy/minute. An age-matched cohort of mice received no IR while additional cohorts received 5 Gy in a single dose, 17.5 Gy in a single dose. RNA was extracted and hybridization done on Affymetrix Mouse430_2 microarrays.
2013-11-01 | E-GEOD-41789 | biostudies-arrayexpress
Project description:We investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation.
2020-09-04 | GSE136899 | GEO
Project description:Analysis of human peripheral blood 48 hours after irradiation ex vivo with graded doses of gamma rays. Results have been used in building and testing classifiers to predict exposure dose for use in radiological triage, and also provide insight into immune cell responses. Results were compared with those from earlier times and from patients exposed in vivo. Peripheral blood from 5 healthy donors was exposed ex vivo to 0. 0.5, 2, 5, or 8 Gy gamma-rays and gene expression was analyzed up to 48 hours after exposure.
2013-09-11 | E-GEOD-44201 | biostudies-arrayexpress
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.
2010-08-05 | E-GEOD-23393 | biostudies-arrayexpress
Project description:Investigation of genome-wide germline copy number mutations in mice after parental exposure to 3 Gy of acute X-rays The level of copy number mutations in offspring of exposed paternal mice was substantially increased when compared to the control Overall 262 samples were used of which 93 were control samples and 169 treated samples. The control samples came from offspring of parents (C57BL6/J (male) and CBA/Ca (female)) with sham -ir while the treated samples were from offspring of 3 Gy whole-body acute irradiated paternal and non-exposed maternal. The treated samples classified into two groups: post-meiotic and pre-meiotic according to exposed status of the sperm that gave rise to the offspring. The reference sample for each offspring was equal mixture of paternal and maternal DNA.
2015-02-04 | E-GEOD-65521 | biostudies-arrayexpress
Project description:Ionizing Radition is known to cause cell damage. Human peripheral blood mononuclear cells have long been used to study radiation induced gene expression profiling. Within this study we evaluated gene and microRNA expression alterations of human PBMC irradiated with 60 Gy g-ray. Cells were cultured for 2, 4 and 20h after irradiation before RNA was isolated and Agilent whole human GenomeOligo Microarray was performed. Radiation induced gene expression in human peripheral blood mononuclear cells were measured at 2, 4 and 20 hours after exposure to doses of 60 Gy g-rays. Non radiated cell of each donor and time point were used as contol cells. Four independent experiments were performed at each time (2, 4, or 20 hours and 0 h - only 1 sample per donor) using 4 different donors.
2014-09-26 | E-GEOD-55953 | biostudies-arrayexpress