Glioblastoma quiescent cells hijack astrocyte-derived mitochondria to drive activation and malignancy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1250475 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Quiescent tumor cell subpopulations at the invasive margin of glioblastoma (GBM) can drive therapeutic resistance, tumor dissemination, and recurrence through phenotypic plasticity. However, the mechanisms underlying their activation remain unclear. This study reveals that reactive astrocytes regulate this critical process via mitochondrial transfer. Specifically, Shmt2 enzyme in astrocytic mitochondria catalyzes one-carbon metabolic products, which significantly promote synthetic metabolic reprogramming and activation of quiescent GBM cells through intercellular mitochondrial transfer. Mechanistic analyses show that tumor cells acquiring astrocytic mitochondria exhibit two key features: (1) Enhanced one-carbon metabolism drives global hyperactive anabolic metabolism through YTHDC1-mediated transcriptional pause release of ribosomal genes; (2) Acquisition of immune-evasive phenotypes and mesenchymal/astrocyte-like characteristics. Genetic experiments further demonstrate that inhibiting astrocytic mitochondrial serine catabolic enzyme SHMT2 or blocking mitochondrial transfer markedly suppresses quiescent GBM cell activation and tumor progression. These findings elucidate a novel mechanism by which astrocytes in the tumor microenvironment drive GBM malignancy through metabolic symbiosis.
2025-04-30 | GSE294545 | GEO
Project description:In our study, astrocytes were proven to be capable of delivering mitochondria to endothelial cells, and thus regulate the integrity of blood-brain barrier. We utilized RNA seq to investigate the effect of astrocyte-derived mitochondria on endothelial cells.
2024-07-31 | GSE206414 | GEO
Project description:CHMP2B mutant astrocytes revealed an accumulation of autophagosomes, which trigger the observed astrocyte reactivity leading to increased cytokine release, altered mitochondria dynamics and metabolic changes.
2021-10-04 | GSE141388 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE8542: BY4742 Quiescent and Non-quiescent replicates GSE8558: Proteinase K treatment of Q and NQ cells GSE8559: S288c Quiescent and Non-quiescent replicates GSE8560: Mutant1 GSE8561: Mutant2 Refer to individual Series
2010-05-29 | E-GEOD-8624 | biostudies-arrayexpress
Project description:Gene expression after mammosphere culture, quiescent single cells
| EGAD00010001964 | EGA
Project description:MartínJiménez2017 - Genome-scale reconstruction of the human astrocyte metabolic network
This model is described in the article:
Genome-Scale Reconstruction
of the Human Astrocyte Metabolic Network.
Martín-Jiménez CA,
Salazar-Barreto D, Barreto GE, González J.
Front Aging Neurosci 2017; 9: 23
Abstract:
Astrocytes are the most abundant cells of the central
nervous system; they have a predominant role in maintaining
brain metabolism. In this sense, abnormal metabolic states have
been found in different neuropathological diseases.
Determination of metabolic states of astrocytes is difficult to
model using current experimental approaches given the high
number of reactions and metabolites present. Thus, genome-scale
metabolic networks derived from transcriptomic data can be used
as a framework to elucidate how astrocytes modulate human brain
metabolic states during normal conditions and in
neurodegenerative diseases. We performed a Genome-Scale
Reconstruction of the Human Astrocyte Metabolic Network with
the purpose of elucidating a significant portion of the
metabolic map of the astrocyte. This is the first global
high-quality, manually curated metabolic reconstruction network
of a human astrocyte. It includes 5,007 metabolites and 5,659
reactions distributed among 8 cell compartments,
(extracellular, cytoplasm, mitochondria, endoplasmic reticle,
Golgi apparatus, lysosome, peroxisome and nucleus). Using the
reconstructed network, the metabolic capabilities of human
astrocytes were calculated and compared both in normal and
ischemic conditions. We identified reactions activated in these
two states, which can be useful for understanding the
astrocytic pathways that are affected during brain disease.
Additionally, we also showed that the obtained flux
distributions in the model, are in accordance with
literature-based findings. Up to date, this is the most
complete representation of the human astrocyte in terms of
inclusion of genes, proteins, reactions and metabolic pathways,
being a useful guide for in-silico analysis of several
metabolic behaviors of the astrocyte during normal and
pathologic states.
This model is hosted on
BioModels Database
and identified by:
MODEL1608180000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1608180000 | BioModels
Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.
2024-06-16 | GSE235060 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276177 | GEO
Project description:Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Post-therapy relapse, particularly driven by leukemic stem cells (LSCs), contributes to therapeutic failure and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and identified potential vulnerabilities for therapeutic intervention. We found that quiescent AML cells, enriched for LSC functions, exhibited a distinct gene set that served as a significant prognostic factor for poor outcomes in AML patients. Furthermore, quiescent cells displayed heightened autophagic activity, with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4), for iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML.
2024-06-13 | PXD042796 | Pride