Single-cell sequencing reveal transformation of neural stem cells into tumor-promoting cells mediated by extracellular vesicles derived from glioblastoma
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ABSTRACT:
PROVIDER: PRJNA564134 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10075617.fastq.gz | Fastqsanger.gz | |||
| SRR10075618.fastq.gz | Fastqsanger.gz | |||
| SRR10075619.fastq.gz | Fastqsanger.gz |
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Project description:We use transcriptome single-cell sequencing to clarify the transformation of neural stem cell into tumor-promoting cells induced by glioblastoma extracellular vesicles. We found several key genes and re-direction of signaling pathway may be involved in the transformation
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Project description:Glioblastoma-derived extracellular vesicles facilitate transformation of astrocytes via reprogramming oncogenic metabolism
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Project description:Background: Glioblastoma (GBM) may arise from brain astrocytes through a multistep process that occurs by the temporal accumulation of genetic mutations. Here, we explore whether GBM-derived extracellular vesicles (EVs) may facilitate neoplastic transformation and malignant growth of astrocytes. Methods: We utilized conditioned medium (CM) of glioma cell and stem cell, its sequential filtration, diverse cell-based assays, RNA sequencing, and metabolic assays to compare the effects of EV-containing and EV-depleted CM on the transformation of human and mouse astrocytes in vitro and tumor growth in vivo. Results: GBM EVs facilitated the neoplastic growth of astrocytes pre-transformed by oncogenic mutations or viruses but were unable to transform normal human and mouse astrocytes. GBM EVs induced proliferation, self-renewal, and colony formation of pre-transformed astrocytes, and enhanced astrocytoma growth in a mouse allograft model. Analysis of extracellular RNAs (exRNAs) in GBM identified multiple full-length mRNAs encoding ribosomal proteins, oxidative phosphorylation, and glycolytic factors. GBM EVs appear to reprogram astrocyte metabolism by inducing a shift in gene expression that may be partly associated with EV-mediated mRNA transfer from glioma cells. Conclusions: Our study suggests a novel EV/exRNA-mediated mechanism contributing to astrocyte transformation via metabolic reprograming and implicates horizontal mRNA transfer in this process.
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Project description:The heterogeneous nature of glioblastoma stem-like cells (GSCs) creates hurdles in developing effective therapies against glioblastoma, making it extremely difficult to eradicate. In this part of the project, we investigated the potential role of GSCs-derived small extracellular vesicles (sEVs) in glioblastoma heterogeneity, plasticity, and aggressiveness with the particular focus on their complexity in term of proteins. Proteome profiling of sEVs and their respective cell lines showed that GSCs-derived sEVs retain their subtype characteristics and are enriched in proteins playing a role in amino acids, carboxylic acids, organic acids transmembrane transport, and growth factor binding. In summary, we revealed the protein content of GSCs-derived sEVs and unveiled their potential contribution to tumor heterogeneity and critical cellular processes commonly deregulated in glioblastoma.
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Project description:The protein Lgl has key roles in the regulation of cell polarity. We have shown that Lgl is inactivated by hyperphosphorylation in glioblastoma as a consequence of PTEN loss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell differentiation. Lgl is phosphorylated by atypical protein kinase C in a complex with Par6 and either activated Cdc42 or activated Rac. Here we have investigated the role of specific Rac guanine nucleotide exchange factors in Lgl hyperphosphorylation in glioblastoma. We used CRISPR/Cas9 to knockout PREX1, a PI 3-kinase pathway-responsive Rac guanine nucleotide exchange factor that is overexpressed in glioblastoma. Knockout of PREX1 in patient-derived glioblastoma cells resulted in a reduction in Lgl phosphorylation and this could be reversed by re-expressing PREX1. PREX1 knockout cells showed reduced motility and altered phenotype suggestive of partial neuronal differentiation; consistent with this, RNA-seq analyses of these cells identified sets of PREX1-regulated genes with roles in promoting cell motility and repressing neuronal differentiation. Knockout of PREX1 in glioblastoma cells derived from a second patient did not affect Lgl phosphorylation. These cells overexpressed a short isoform of the Rac guanine nucleotide exchange factor TIAM1; knockdown of TIAM1 in PREX1-knockout cells from this patient reduced Lgl phosphorylation. These data show that PREX1 links aberrant PI 3-kinase to Lgl phosphorylation in glioblastoma, but that TIAM1 can also promote Lgl phosphorylation in a subset of patients. While this shows redundant mechanisms for Lgl phosphorylation, PREX1 appears to have a non-redundant role in glioblastoma cell motility, as this was impaired in PREX1 knockout cells from both patients.
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Project description:CD73 (ecto-5'-nucleotidase) is a metabolic immune checkpoint that dephosphorylates AMP to produce adenosine. Adenosine plays a pivotal role in immunosuppressive tumor microenvironment (TME) through adenosine receptors expressed on various immune cells. AB680, a specific CD73 inhibitor, is currently undergoing clinical trials for highly refractory cancers. In this study, we investigated the antitumor effects and mechanisms of AB680 in glioblastoma (GBM). By analyzing the expression pattern of CD73 across all cell types in orthotopic naïve G422<sup>TN</sup>-GBM tumors (d 7), we found that CD73 and its associated adenosine metabolic signaling were significantly elevated in G422<sup>TN</sup>-GBM cells compared to all other cell types. High CD73 expression was also observed in human GBM samples and was correlated with shorter patient survival. Administration of AB680 significantly prolonged survival in G422<sup>TN</sup>-GBM-bearing mice, reduced tumor size, cell proliferation, angiogenesis, and enhanced microglia activation and anti-tumor immune responses. Metabolomic analysis revealed that AB680 markedly increased ADP and AMP levels in the TME of orthotopic G422<sup>TN</sup>-GBM, thereby stimulating the activation of P2RY12<sup>+</sup> microglia to exert their M1-like anti-cancer functions, as confirmed by human GBM scRNA-seq and G422<sup>TN</sup>-GBM snRNA-seq data. Furthermore, AB680 combined with RT/TMZ exhibited synergistic therapeutic effects by reversing RT/TMZ-induced increases in adenosine levels and promoting the transformation of P2RY12<sup>+</sup> microglia. Overall, this study demonstrates that targeting CD73 with AB680 alters purine metabolism in the GBM microenvironment, promotes the transformation of P2RY12<sup>+</sup> microglia, and triggers robust anti-tumor immune responses. These results support the rationale for AB680-based therapeutic clinical trials for GBM.
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Project description:How cancer cells adapt to hypoxia during tumor development remains an important question. The hypothesis tested in the present study was that tumor cell-derived exosome vesicles (also known as microvesicles or extracellular vesicles) are mediators of hypoxia-dependent intercellular signaling in glioblastoma (GBM), i.e. highly aggressive brain tumors characterized by hypoxia and a vascular density that is among the highest of all human malignancies. In vitro hypoxia experiments and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins, several of which were associated with poor patient prognosis. We show that cancer cell exosomes mediate hypoxia-dependent, phenotypic modulation of stromal cells in vitro and ex vivo, resulting in accelerated GBM tumor angiogenesis and growth in mice. These data suggest that exosomes constitute potent mediators of hypoxia-driven tumor development, and circulating multiparameter biomarkers of tumor hypoxia. U87 MG glioblastoma cells were grown at normoxic (21% oxygen) or hypoxic (1% oxygen) conditions for 48 hours. Conditioned media from normoxic and hypoxic cells were then used to isolate exosomes by differential centrifugation. Both cells and exosomes were lysed in Trizol reagent, and RNA was isolated.Total RNA from all samples (four types of samples in three biological repilicates) was subjected to genome-wide transcriptional analysis with Illumina HumanHT-12 V3.0 expression beadchip. Gene expression profile obtained from hypoxic U87 MG glioblastoma cells was compared to the profile of normoxic control cells. Analogically, gene expression profile obtained from hypoxic U87 MG cells was compared to the profile of exosomes secreted by normoxic U87 MG cells.
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