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Bulk RNA-sequencing results of p16INK4A-high and -low glioblastoma, IDH-wild type, grade 4.

ABSTRACT: The expression of p16INK4A is widely used to identify fully senescent cells in noncancerous tissues, as well as senescent cancer cells in various types of cancer. In our study, we observed diffuse expression of p16INK4A in around 40 % of the patients with wild-type CDKN2A gene without mutation showing senescence phenotype, correlating with significant differences in overall survival between patients with high and low levels of p16INK4A expression. This prognostic distinction led us to hypothesize that cellular senescence in glioblastoma cells might confer a favorable effect on patient outcomes. To investigate the mechanism underlying this phenotype, we conducted RNA sequencing on 11 samples of glioblastoma, IDH-wild type along with corresponding in vivo and in vitro studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266210 | GEO | 2024/05/10

REPOSITORIES: GEO

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ADAR1 downregulation contributes to p16INK4a upregulation independent of RNA editing during senescence

Project description:Cellular senescence plays a causal role in ageing and, in mouse, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders. Adenosine deaminases acting on RNA (ADARs) RNA editing enzymes are also implicated as important regulators of human ageing and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through upregulating p16INK4a. ADAR1 is downregulated during senescence post-transcriptionally by autophagy-lysosomal pathway and the downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a dependent and independent of its RNA editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA binding protein that increases the half-life and steady state levels of its target mRNAs. And SIRT1, in turn, antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4aupregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary, and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing independent role of ADAR1 in regulating senescence by post-transcriptionally controlling p16INK4a expression.

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Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

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Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung [RNA-Seq]

Project description:We collected freshly sorted mesenchyme (live CD45-Epcam-CD31-PDGFRa+GFP- or GFP+) from dissociated lung tissue of INKBRITE animals to characterize the transcriptome difference between p16INK4a+ vs p16INK4a- cells at homeostasis and during injury. We used fluorescence activated cell sorting (FACS) to exclude immune (CD45+), epithelial (Epcam+), and endothelial (CD31+) cells and positively select for PDGFRa+ mesenchyme. Cells were sequenced at a depth of average of 45 million reads/sample. The results revealed an increase of senescence associated secretory phenotype (SASP) signature in p16INK4+ cells that becomes refined after injury. We found the expression of an epithelial growth factor epiregulin (ereg) increased in p16INK4a+ cells after injury suggesting a possible role of p16INK4a+ senescence during regeneration of lung epithelium.

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Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A

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REST transcription factor holds the balance between the invasion and cell differentiation in IDH-mutant and IDH-wild type gliomas

Project description:Glioblastoma is the deadliest brain tumor with median survival of 15 months due to diffusive growth and lack of efficient therapy. Recurrent mutations in genes coding for isocitrate dehydrogenases (IDH) 1 or 2 cause to a change in function of the enzymes, resulting in production of 2-hydroxyglutarate, which leads to DNA hypermethylation phenotype, affecting transcription activators/repressors binding to DNA and gene expression. REST is a canonical repressor of neuronal genes in non-neuronal cells, whose levels differ between IDH wt and mut gliomas and whose expression levels correlate with the patients’ survival probability.

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Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [10X scRNA-seq]

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Genotyping by array of 123 IDH WT glioblastomas

Project description:Glioblastoma (GBM) is the most frequent and most aggressive form of diffuse glioma. The prognosis is very poor, with a median overall survival of 15 months after maximum safe resection and radiochemotherapy.GBM is one of the most genetically unstable cancers. It is characterized by numerous chromosome (chr) copy number alterations (CNA), such as chr 7 gain, chr 9p loss, and chr 10 loss, along with CDKN2A homozygous deletion (chr 9p21) and EGFR amplification (chr 7p11).Chromosome instability (CIN) may be the cause or the consequence of GBM development. In high-grade diffuse gliomas (HGG), CIN may initiate tumorigenesis. To identify recurrent genomic abnormalities in IDH WT glioblastomas, SNP arrays (Illumina 850K CytoSNP) were analyzed for 123 IDH WT GBM cases.

2018-02-27 | E-MTAB-6371 | biostudies-arrayexpress

Transcriptome-profiling (RNA-seq) and Ribosome-profiling (Ribo-seq) in proliferation, quiescence, senescence and transformed states.

Project description:We applied in parallel RNA-Seq and Ribosome-profiling analyses to immortalized human primary BJ fibroblast cells under the following conditions: normal proliferation, quiescence (induced by serum depletion), senescence (induced by activation of the oncogenic RASG12V gene, and examined at early (5 days; pre-senescent state) and late (14 days; fully senescent state) time points), and neoplastic transformation (induced by RASG12V in the background of stable p53 and p16INK4A knockdowns and SV40 small-T expression. RNA-seq, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed. Ribosome profiling, using Illumina HiSeq 2000, was applied to BJ cells under 5 conditions: proliferation, quiescence, pre-senescence, full-senescence, and transfomed.

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