A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes
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PROVIDER: PRJNA494558 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) is the most aggressive and common malignant brain tumor in adults. GBMs are characterized by high intratumor heterogeneity and by the presence of the cancer stem cell niche. The vacuolar ATPase (V-ATPase) is a multisubunit proton pump that plays a role in multiple processes in eukaryotic cells. Altered V-ATPase activity is associated with several human diseases and in cancer may play relevant role due the acidification of cellular organelles, such as, endosomes and lysosomes. We identified overexpression of the V-ATPase V1G1 subunit in GBM derived neurospheres (NS), a cell subpopulation enriched in cancer stem cells. Interestingly GBM NS secrete different types of vesicles, including large oncosomes (LO) thereby influencing their microenvironment. Herein, we assessed the transcriptome of non-sphere forming glioma cells (n=2 pairs) cocultured with LO or empty media (mock) by microarray to identify pathways associated with the LO-induced reprogramming ability. Gene set enrichment analysis (GSEA) revealed that LO-supplemented cultures activated a number of cancer-related pathways, including those involved in glioma V-ATPase-related signaling (Notch, mTOR, and lysosomal transport), as well as cell proliferation and cell transcription programs.
2019-05-10 | GSE120793 | GEO
Project description:BackgroundThe V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.MethodsLarge oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.FindingsGBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.InterpretationWe identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).
| S-EPMC6441844 | biostudies-literature
Project description:Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. The purpose of the present study was to identify GBM cell-selective secreted proteins by analyzing conditioned media (CM) from GBM, breast, and colon cancer cell lines using sequential window acquisition of all theoretical spectra mass spectrometry (SWATH-MS) and targeted proteomics. We identified 26,041 peptides derived from 2,371 proteins in the CM from GBM and the other cancer cell lines. Among the proteins identified, 15 showed significantly higher expression in the CM from GBM cell lines than in those from other cancer cell lines.
2020-09-19 | PXD016898 | JPOST Repository
Project description:We identified a subgroup of patient-derived glioblastoma (GBM) cells that express high levels of the neurogenic transcription factor, ASCL1, which predicts response to pharmacological inhibition of the Notch signaling pathway. Treatment of ASCL1hi GBM cells with a Notch signaling inhibitor induced a change in cell fate from neoplastic to neuronal. Importantly, acquisition of the neuronal fate was accompanied by a reduction in tumorigenic potential. Loss of ASCL1 in GBM cells rendered cells no longer responsive to Notch signaling inhibition and we determined ASCL1 is required for the competency of GBM cells to undergo neuronal differentiation. Enforced ASCL1 expression directed GBM cells towards a neuronal cell fate reminiscent of terminal differentiation. RNA-seq analysis of GBM cells treated with the Notch signaling inhibitor reveals neuronal target gene activation is associated with increased stoichiometric levels of ASCL1, suggesting threshold levels of ASCL1 in GBM cells governs neuronal differentiation. We demonstrate that neoplastic cells which retain expression of key neurogenic programs can have their fates redirected towards terminal differentiation. Directed fate specification to neuronal cell types by exploiting latent neurogenic programs may be a strategy to treat a subset of GBM patients. Our findings therefore highlight the potential of differentiation therapy for a subset of molecularly defined GBMs.
2017-07-21 | GSE96088 | GEO
Project description:V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans
| PRJNA744137 | ENA
Project description:In this study, we investigated and compared the miRNA and protein content of the small EVs released by different human GBM established cell lines and by GBM primary CSC lines, to explore the role of EVs in their different tumor behavior and capacities.
2022-01-11 | MSV000088671 | MassIVE
Project description:To adapt mitochondrial function to the ever-changing intra- and extra-cellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1, and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components, but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.
2022-09-23 | GSE179517 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24446: Genetic abnormalities in GBM brain tumors GSE24452: Genetic abnormalities in various cell subpopulations of GBM brain tumors GSE24557: Exon-level expression profiles of GBM brain tumors Refer to individual Series
2010-11-21 | E-GEOD-24558 | biostudies-arrayexpress
Project description:GBM is a heterogenous tumor. Based on membrane protein expression, the GBM single cell dissociates were seperated into different subfractions by FACS assay. The genomic aberration among each populations were compared by analysis of CGH data. Genomic DNA were extracted from sorted cell population and CGH assay were performed to compare the similarity genomic abnormality among different cell groups.
2010-11-21 | E-GEOD-24452 | biostudies-arrayexpress
Project description:Glioblastoma multiforme (GBM) is the most aggressive form of brain tumors. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to such treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and -5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased of cell proliferation, and increased cell cycle arrest and apoptosis in comparison to only irradiated cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation and cell cycle regulation. To our knowledge, this is the first study to describe role of miR-338-5p in GBM and its potential to improve sensitivity of GBM to radiation. Study was performed on three glioblastoma multiforme cell lines A172, T98G and U87MG. This experiment was performed on Affymetrix GeneChip Human Gene ST 1.0 to elucidate the targets of miRNA-338-5p. Cell lines were seeded 24 hours prior transfection. After transfection with pre-miR338-5p or negative control cell were cultured for 24 hours and harvested. RNA was isolated using MirVana miRNA Isolation Kit (Ambion, USA) and checked for RNA integrity by Bioanalyzer 2100 and purity by ratios 260/280>1.8 and 260/230>1.8 by Nanodrop2000.
2015-12-10 | E-GEOD-75789 | biostudies-arrayexpress