Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
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PROVIDER: PRJNA1004603 | ENA |
REPOSITORIES: ENA
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Project description:Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
| PRJNA1004206 | ENA
Project description:Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression
| PRJNA1004600 | ENA
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:This SuperSeries is composed of the SubSeries listed below.
2023-12-01 | GSE240676 | 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.
2014-01-17 | GSE36940 | GEO
Project description:The neural behavior of glioblastoma, including the formation of tumor microtubes and synaptic circuitry, is increasingly understood to be pivotal for disease manifestation (Osswald et al. 2015; Venkatesh et al. 2015; Weil et al. 2017; Venkataramani et al. 2019; Venkatesh et al. 2019; Alcantara Llaguno et al. 2019; Venkataramani et al. 2022). Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across 27 glioblastoma patients and diverse model systems. In patient tumor samples taken directly after surgery, we identify a spectrum of neural stem cell morphologies indicative of poor prognosis, and discover a set of repurposable neuroactive drugs with unexpected and consistent anti-glioma efficacy. Glioblastoma cells exhibit functional dependencies on highly expressed drug targets including neurological ion channels and receptors, while interpretable molecular machine learning reveals downstream convergence on secondary drug targets (COSTAR) involving AP-1-driven tumor suppression. COSTAR enables in silico drug screening on >1 million compounds that are validated with high accuracy. Multi-omic profiling of drug-treated glioblastoma cells confirms rapid Ca2+-driven AP-1 pathway induction to represent a tumor-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Finally, the consistent anti-glioma activity across patients and model systems is epitomized by the antidepressant Vortioxetine, which synergizes in vivo with approved glioblastoma chemotherapies. In all, our global analysis reveals that the neural vulnerabilities of glioblastoma converge on an AP-1 mediated gene regulatory network with direct translatable potential.
2024-08-01 | PXD037015 | panorama
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
Project description:We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
| EGAS00001003493 | EGA