Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment
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ABSTRACT:
PROVIDER: PRJNA526715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8715441_1.fastq.gz | Fastqsanger.gz | |||
| SRR8715441_2.fastq.gz | Fastqsanger.gz | |||
| SRR8715442_1.fastq.gz | Fastqsanger.gz | |||
| SRR8715442_2.fastq.gz | Fastqsanger.gz | |||
| SRR8715443_1.fastq.gz | Fastqsanger.gz |
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Project description:Cancer stem cells (CSCs) have been proposed to underlie the hierarchical organization of Glioblastoma (GBM) causing resistance to treatment, however the identity of CSCs in solid tumors remains largely elusive. Here we find that GBM cells expressing cell membrane CSC-associated markers do not represent a clonal entity defined by distinct functional properties and/or transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions that are instructed by the microenvironment. While all tested cancer cell subpopulations survive and adjust their phenotype in vivo, their speed of plasticity differs resulting in variable tumor growth rates. Thus CSC-associated phenotypic heterogeneity is a result of stochastic reversible plasticity and increased tumorigenic potential in vivo correlates with fast adapting cell states.
2019-03-26 | GSE128195 | GEO
Project description: Not available
| S-EPMC6467886 | biostudies-literature
Project description:Glioblastoma, the most frequent primary malignant brain tumor in adults, is characterized by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumor cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. We have previously shown that the peroxisome proliferator–activated receptor γ coactivator (PGC)-1α is a key regulator of cellular respiration, proliferation and invasion in glioblastoma. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (PGC-1α stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of adenosine monophosphate kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity towards non-glucose nutrients including galactose, fatty acids and ketone bodies. Moreover, spatially resolved multi-omic analysis integrating transcriptomics and matrix-assisted laser desorption/ionization (MALDI) was used to correlate the gene expression pattern of PGC-1α with local metabolic and genetic architecture in human glioblastoma tissue sections. A nutrient switch from glucose to galactose, ketone bodies or fatty acids triggered an initial activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs towards mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under non-glucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with non-hypoxic tumor niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs which result in upregulation of the enzymatic machinery necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data from human glioblastoma samples confirms the relevance of PGC-1α especially in non-hypoxic tumor regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.
2025-01-19 | PXD046679 | Pride
Project description:The nervous system has a tremendous capacity for experience-dependent plasticity. In response to changes in activity induced by environmental cues, many types of neurons undergo a process known as homeostatic plasticity, which serves to maintain overall network function in the face of mounting experience-dependent changes in synaptic strengths. Homeostatic plasticity involves both changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in both animal models and in human patients. However, it is not known whether homeostatic plasticity is engaged in sensory neurons under normal conditions or whether dysfunction in these homeostatic mechanisms might contribute to the pathophysiology of chronic pain. To address these questions, we tested the impact of sustained depolarization on various measures of excitability in mouse and human sensory neurons. Depolarization induced by 30mM KCl induces a compensatory decrease in the excitability of both mouse and human sensory neurons. Moreover, we also find that voltage-gated sodium currents are robustly inhibited in mouse sensory neurons after chronic depolarization, thus contributing to the overall decrease in neuronal excitability and serving as a potential regulatory mechanism to drive intrinsic neuronal homeostatic control. Our results indicate that mouse and human sensory neurons undergo homeostatic regulation of intrinsic excitability in response to sustained depolarization. Decreased efficacy of these homeostatic mechanisms could potentially contribute to the development of pathological conditions, including chronic pain.
2024-01-31 | GSE236109 | 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.
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Project description:Intrinsic Homeostatic Plasticity in Mouse and Human Sensory Neurons
| PRJNA989045 | ENA
Project description:<p>Transcriptomic studies attempted to classify glioblastoma (GB) into subtypes that predict survival and that have different therapeutic vulnerabilities1-3. Here we identified three metabolic subtypes: glycolytic, oxidative and a mixed glycolytic/oxidative by mass spectrometry imaging of rapidly excised tumour sections from two GB patients infused with [U-13C]glucose and from spatial transcriptomic analysis of contiguous sections. The phenotypes are not correlated with microenvironmental features, including proliferation rate, immune cell infiltration and vascularisation, are retained when patient-derived cells are grown in vitro, or as orthotopically implanted xenografts, and are robust to changes in oxygen concentration, demonstrating their cell intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes are large enough to be detected using clinically applicable metabolic imaging techniques. A limitation of the study is that it is based on only two patient tumours, albeit on multiple sections, and therefore represents a proof-of-concept study.</p>
2025-05-08 | MTBLS12176 | MetaboLights
Project description:Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma
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Project description:Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma.
| PRJNA658688 | ENA
Project description:BCAT1 regulates glioblastoma cell plasticity and contributes to immunosuppression
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