Similar Datasets
Project description:The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecasts how tumor cells organize to sustain growth and identifies the rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA-related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt-antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases the overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte-like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.
2023-12-01 | GSE240675 | GEO
Project description:The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecasts how tumor cells organize to sustain growth and identifies the rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA-related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt-antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases the overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte-like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.
2025-08-08 | GSE240541 | GEO
Project description:Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
| PRJNA1004600 | ENA
Project description:Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
| PRJNA1004206 | ENA
Project description:Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
| PRJNA1004603 | ENA
Project description:We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including CD276 We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
| S-EPMC6673710 | biostudies-literature
Project description:Focal amplification of epidermal growth factor receptor (EGFR) and its ligand-independent, constitutively active EGFRvIII mutant form are prominent oncogenic drivers in glioblastoma (GBM). The EGFRvIII gene rearrangement is considered to be an initiating event in the etiology of GBM, however, the mechanistic details of how EGFRvIII drives cellular transformation and tumor maintenance remain unclear. Here, we report that EGFRvIII demonstrates a reliance on PDGFRA co-stimulatory signaling during the tumorigenic process in a genetically engineered autochthonous GBM model. This dependency exposes liabilities that were leveraged using kinase inhibitors treatments in EGFRvIII-expressing GBM patient-derived xenografts (PDXs), where simultaneous pharmacological inhibition of EGFRvIII and PDGFRA kinase activities is necessary for anti-tumor efficacy. Our work establishes that EGFRvIII-positive tumors have unexplored vulnerabilities to targeted agents concomitant to the EGFR kinase inhibitor repertoire.
| S-EPMC9159289 | biostudies-literature
Project description:(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM.
| S-EPMC7836009 | biostudies-literature
Project description:The determinants of the genetic complexity of Glioblastoma are poorly understood. We generated murine Glioblastomas by transforming glial progenitors in the adult brain with PDGF expression and PTEN deletion +/- p53 deletion. PDGF+PTEN-/- tumors developed additional deletions of specific genes in up to 100% of the tumors, whereas PDGF+PTEN-/-p53-/- tumors did not. Cross-species comparison with data from tCGA database and published in Verhaak, 2010, showed that consistent genetic deletions observed in mouse tumors were specific to human Proneural Glioblastoma. These findings show that the genetic alterations that accumulate during tumor progression are determined by the initiating genetic alterations and by the cellular context in which they occur.
2014-01-17 | GSE36940 | GEO
Project description:The determinants of the genetic complexity of Glioblastoma are poorly understood. We generated murine Glioblastomas by transforming glial progenitors in the adult brain with PDGF expression and PTEN deletion +/- p53 deletion. PDGF+PTEN-/- tumors developed additional deletions of specific genes in up to 100% of the tumors, whereas PDGF+PTEN-/-p53-/- tumors did not. Cross-species comparison with data from tCGA database and published in Verhaak, 2010, showed that consistent genetic deletions observed in mouse tumors were specific to human Proneural Glioblastoma. These findings show that the genetic alterations that accumulate during tumor progression are determined by the initiating genetic alterations and by the cellular context in which they occur. Murine gliomas were induced in vivo by retroviral mediated PDGF overexpression, PTEN deletion with or without p53 deletion using Cre/lox system. Tumors were subsequently harvested for sequencing and aCGH analysis. Paired liver DNA was used for hybridization. For PDGF+PTEN-/- tumors, different timepoints were obtained including 21, 35 days post tumor induction, as well as endstage tumors.
2014-01-17 | E-GEOD-36940 | biostudies-arrayexpress