Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE168039 | GEO | 2022/12/15
REPOSITORIES: GEO
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Project description:GBM mouse model: The goal of this study is to compare the transcriptomic landscape at the endpoint of GBMs upon senescent cells deletion. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) upon ganciclovir (GCV) injection. We compared p16-3MR+GCV GBMs to two control conditions, either WT+GCV or p16-3MR+GCV. We showed a slight decreased of p16Ink4a transcripts in p16-3MR+GCV compared to WT+GCV GBMs and GSEA demonstrated significant down-regulation of senescence pathways in p16-3MR+GCV GBMs compared to control GBMs. GBM-derived organoids: We used a mouse GBM-derived organoids model to further explore the function of Nrf2, that we identified as one potential trigger of the pro-tumoral action of p16Ink4a Hi malignant cells. We compared GBM-derived organoids treated with the senolytic ABT263 (Navitoclax; inhibitor of the anti-apoptotic proteins Blcl2 and BCL-xL) or vehicle (vhc) after 14 days in culture. We validated ABT263 efficacy via the significant downregulation of the expression of p16Ink4a, p15Ink4b and p21Cip1 senescent markers. We further identified upon senolytic treatment, downregulated genes encoding for SASP. Importantly, GSEA revealed a significant downregulation of Nrf2 pathway upon senolytic treatment.
2022-12-15 | GSE168037 | GEO
Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs, at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared two p16-3MR+GCV to two WT+GCV control GBMs that were harvested 7 days after the last GCV injection. p16Ink4a Hi senescent cells were a subset of malignant cells, mostly grouped in the astrocyte cluster and to a lesser extend in the NP-like cluster. We also found that p16Ink4a Hi senescent cells deletion modifies the cell state of malignant cells and modulates the tumor microenvironment. This study allowed us to define a GBM senescence signature.
2022-12-15 | GSE168038 | GEO
Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs and characterize their action on the tumor microenvironment at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared p16-3MR+GCV to WT+GCV control GBMs that were harvested 7 days after the last GCV injection.
2022-12-15 | GSE198439 | GEO
Project description:The goal of this transcriptomic analysis is to decipher whether NRF2 pathway plays a role in the induction of pro-tumoral senescence in glioblastoma (GBM).
2022-12-15 | GSE198438 | GEO
Project description:Malignant gliomas represent the most devastating group of brain tumors in adults, among which glioblastoma multiforme (GBM) exhibits the highest malignancy rate. Despite combined modality treatment, GBM recurs and is invariably fatal. A further insight into molecular background of gliomagenesis is required to improve patient outcome. The first aim of this study was to gain broad information on miRNA expression pattern in malignant gliomas, mainly GBM. We investigated the global miRNA profile of malignant glioma tissues by means of miRNA microarrays, deep sequencing and meta-analysis. We selected miRNAs the most frequently deregulated in glioblastoma tissues as well as peritumoral brain areas in comparison to normal human brain. We found candidate miRNAs contributing to progression from gliomas grade III to gliomas grade IV. The meta-analysis of miRNA profiling studies in GBM tissues summarizes the past and recent advances in an investigation of miRNA signature in GBM versus noncancerous human brain and provides a comprehensive overview. We proposed a set of 35 miRNAs which expression is the most frequently deregulated in GBM patients and 30 miRNA candidates recognized as novel GBM biomarkers. miRNA expression profile in the adult malignant gliomas, glioma peritumoral tissues and normal human brain.
2014-09-26 | E-GEOD-61710 | biostudies-arrayexpress
Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Keywords: SuperSeries DNA copy number and mRNA transcriptome of human glioblastoma tumors were profiled using Agilent and Affymetrix microarrays. This SuperSeries is composed of the following subset Series: GSE7602: Human GBM tumor vs Normal Human DNA GSE9171: Expression data from human GBM tumors and cell lines GSE9177: Human GBM tumor vs Normal Human DNA
2008-04-29 | E-GEOD-9200 | biostudies-arrayexpress
Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Keywords: comparative genomic hybridization DNA copy number abberation of human glioblastoma tumors were obtained by comparative genomic hybridization of GBM tumor vs. normal human DNA. 11 human GBM samples were analyzed on Agilent human 244A human cgh array (G4411B). Normal Human DNA was used as reference. Some samples were hybridized with dye-swap replica.
2008-04-29 | E-GEOD-9177 | biostudies-arrayexpress
Project description:Malignant gliomas represent the most devastating group of brain tumors in adults, among which glioblastoma multiforme (GBM) exhibits the highest malignancy rate. Despite combined modality treatment, GBM recurs and is invariably fatal. A further insight into molecular background of gliomagenesis is required to improve patient outcome. The first aim of this study was to gain broad information on miRNA expression pattern in malignant gliomas, mainly GBM. We investigated the global miRNA profile of malignant glioma tissues by means of miRNA microarrays, deep sequencing and meta-analysis. We selected miRNAs the most frequently deregulated in glioblastoma tissues as well as peritumoral brain areas in comparison to normal human brain. We found candidate miRNAs contributing to progression from gliomas grade III to gliomas grade IV. The meta-analysis of miRNA profiling studies in GBM tissues summarizes the past and recent advances in an investigation of miRNA signature in GBM versus noncancerous human brain and provides a comprehensive overview. We proposed a set of 35 miRNAs which expression is the most frequently deregulated in GBM patients and 30 miRNA candidates recognized as novel GBM biomarkers.
2014-09-26 | GSE61710 | GEO
Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Experiment Overall Design: Expression profiles of human glioblastoma frozen tumors and cell lines were obtained to study copy number abberation driven expressin alteration. Experiment Overall Design: Affymetrix human genome U133plus2 arrays were used to obtain the expression profiles of human glioblastoma tumors and cell lines.
2008-06-16 | E-GEOD-9171 | biostudies-arrayexpress
Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Keywords: static expression
2008-04-29 | GSE9171 | GEO