Horizontal mitochondrial transfer from microenvironment increases glioblastoma tumorigenicity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183004 | GEO | 2021/08/31
REPOSITORIES: GEO
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Project description:Horizontal mitochondrial transfer from microenvironment increases glioblastoma tumorigenicity
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Project description:Glioblastoma (GBM), the most malignant primary brain tumor, is characterized by widespread heterogeneity, leading to poor and unpredictable clinical outcomes. Recent studies have provided evidences that the tumor microenvironment has a critical role in regulating tumor growth by establishing a complex network of interactions with tumor cells. Here we investigate how GBM cells modulate glial cells, and how this modulation can influence back on the malignant phenotype of GBM cells. Primary mouse glial cultures were established and cultured in serum-free media (unprimed) or exposed to secretome derived from GL261 GBM cells (primed). Conditioned media (CM) from each glial culture were collected and a proteomic analysis was conducted. Glial cells CM (unprimed and primed) were also used in GL261 GBM cells to evaluate its impact in critical hallmarks of GBM cells, including viability, migration, and activation of tumor-related intracellular signaling pathways. The proteomic analysis revealed that the pre-exposure of glial cells to CM from GBM cells led to the upregulation of several proteins related to inflammatory response, cell adhesion and extracellular structure organization within the secretome of primed glial cells, consistent with a pattern of reactive astrogliosis. At the functional levels, CM derived from unprimed glial cells favored an increase in cell migration capacity, while CM from primed glial cells was more efficient in promoting GBM cells viability. These effects on GBM cells were accompanied by activation of particular intracellular cancer-related pathways, mainly the MAPK/ERK pathway, which is a known regulator of cell proliferation. Together, our results demonstrate that glial cells can have a different impact on the progression of GBM tumors, suggesting that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the “go-or-grow” phenotypic switch of GBM cells. Together, our results suggest that glial cells can impact on the pathophysiology of GBM tumors, and that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the “go-or-grow” phenotypic switch of GBM cells.
2017-10-09 | PXD006007 | Pride
Project description:Glioblastoma (GBM), the most common malignant tumor originating in the brain remains incurable with few treatment advances despite decades of investigation. Treatment failure is often attributed to intratumoral heterogeneity, which fosters tumor evolution and selection of resistant clones. However, intratumoral heterogeneity and tumor evolution remain poorly understood in GBM as studies are typically based on single tissue biopsies and lack spatial context. Here, we have utilized pre-operative MRI scans and intra-operative 3-D surgical neuronavigation for 10 primary IDH-WT GBM patients to acquire 103 tissue samples that represent maximal tumor diversity and are mapped by 3-D spatial coordinates. We combine insights from deconvolution of GBM transcriptomes and chromatin landscapes with single-cell analysis to assess intratumoral heterogeneity of each program at the cellular level and to distinguish neuronal, glial, and immune programs aberrantly active in tumor cells from their counterparts in normal cells. Collectively, these data provide unprecedented insight into GBM intratumoral heterogeneity and evolution from single-cell to whole-tumor 3D spatial resolution, redefining current understanding and providing a rich resource of targets for therapeutic investigation.
2024-01-18 | GSE226726 | GEO
Project description:Despite the progress in medicine, no significant advancement in the standard of care for glioblastoma (GBM) patients have been reached. GBM heterogeneity, poor blood–brain barrier penetration and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM Tumor-Initiating Cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrate that Lysine-specific histone demethylase 1A (LSD1) is a druggable target in GBM. Here, we analyze the effect of LSD1i treatment on histone H3K4 in primary human cells and mouse brains.
2022-04-14 | PXD025781 | Pride
Project description:Mesenchymal stem cells (MSCs) are cells with high regenerative and immunosuppressive capacity that are known to be very potent donors of functional mitochondria to all surrounding cells, including immune cells. As metabolism shapes immune cell response and phenotype, mitochondrial transfer might be one of the main immunosuppressive mechanisms used by stem cells. However, the precise mechanism underlying horizontal mitochondrial transfer and its effect on some cell populations has yet to be discovered. In our project, we have shown that MSCs transfer mitochondria to B lymphocytes less efficiently in comparison to other immune populations. To describe the effect of mitochondrial transfer on activated B lymphocytes, MSCs were co-cultivated with B lymphocytes which were activated prior to co-cultivation. Then B cell acceptors and non-acceptors of mitochondria were sorted for further RNA isolation and the performance of bulk RNA-seq.
2024-03-02 | E-MTAB-13438 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor. The extracellular matrix (ECM), also known as the matrisome, helps determine glioma invasion, adhesion, and growth. Little attention, however, has been paid to glycosylation of the ECM components that constitute the majority of glycosylated protein mass and presumed biological properties. To acquire a comprehensive understanding of the biological functions of the matrisome and its components, including proteoglycans and glycosaminoglycans (GAGs), in GBM tumorigenesis, and to identify potential biomarker candidates, we studied the alterations of GAGs, including heparan sulfate (HS) and chondroitin sulfate (CS), the core proteins of proteoglycans, and other glycosylated matrisomal proteins in GBM subtypes vs. control human brain tissue samples. We scrutinized the proteomics data to acquire in-depth site-specific glycoproteomic profiles of the GBM subtypes that will assist in identifying specific glycosylation changes in GBM. We observed an increase in CS 6-O sulfation and a decrease in HS 6-O sulfation, accompanied by an increase in unsulfated CS and HS disaccharides in GBM vs. control samples. Several core matrisome proteins, including proteoglycans (decorin, biglycan, agrin, prolargin, glypican-1, CSPG4), tenascin, fibronectin, hyaluronan link protein 1 and 2, laminins, and collagens, were differentially regulated in GBM vs. controls. Interestingly, a higher degree of collagen hydroxyprolination was also observed for GBM vs. controls. Further, two proteoglycans, CSPG4 and agrin, were significantly lower, about 6–fold for IDH-mutant compared to the WT GBM samples. Differential regulation of O-glycopeptides for proteoglycans, including brevican, neurocan, and versican, was observed for GBM subtypes vs. controls. Moreover, an increase in levels of glycosyltransferase and glycosidase enzymes was observed for GBM when compared to control samples. We also report distinct protein, peptide, and glycopeptide features for GBM subtypes comparisons. Taken together, our study informs understanding of the alterations to key matrisomal molecules that occur during GBM development.
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Project description:The purpose of this study is to determine whether the combination of two agents, INC280 and bevacizumab, is safe and effective when administered to patients with Glioblastoma Multiforme (GBM) who have progressed after receiving prior therapy or who have unresectable GBM.
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Project description:phenotypic reprogramming ability of teh zebtafish brain microenviroment on GBM derived cells controlled by the activation of endogenous Wnt pathway Class comparison between different time point of human GBM cells trasplanted into zebrafish
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Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
2022-01-10 | GSE181366 | GEO
Project description:Tumor-initiating cells (TICs) play a critical role in glioblastoma (GBM) maintenance being responsible for its heterogeneity and resistance to standard therapy. A step toward clinical translation includes GBM TIC targeting. Among the molecules tested for GBM treatment, are those targeting epigenetic modifiers. By using patient-derived TICs and xenograft orthotopic models, we identified Lysine-specific histone demethylase 1A (LSD1) as a potentially druggable target in GBM. LSD1-directed therapy by means of the selective, orally bioavailable and brain penetrant inhibitor DDP_38003 effectively impairs growth, stem-like features and tumorigenic potential of GBM TICs. Our findings point to LSD1 as a positive regulator of Activating Transcription Factor 4 (ATF4)-dependent response in all stress conditions arising during tumor growth and therapy. Thus, through the downregulation of either ATF4 and its adaptive genes, LSD1 targeting is likely a promising strategy to hit GBM TICs by counteracting the ATF4-mediated adaptation to stress.
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