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Expression data from patient-derived primary glioblastoma cell lines

ABSTRACT: Genetic alterations that give rise to tumorigenesis result in altered epigenetic and gene expression profiles. We sought to identify and better understand potential consequences of MTAP deletion in glioblastoma by examining gene expression profiles of MTAP deleted and MTAP WT GBM cell lines. MTAP deletion results in accumulation of the abberant metabolite, MTA, with potential consequences to epigenetic regulation and signal transduction. We also examined the cellular response (gene expression) to purine deprivation with L-Alanosine treamment

ORGANISM(S): Homo sapiens

PROVIDER: GSE114867 | GEO | 2020/05/12

REPOSITORIES: GEO

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SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors

Project description:The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors. Metabolic enzymes, together with exchanged substrates and products, have emerged as potential biomarkers and therapeutic targets. However, traditional techniques for profiling secreted metabolites in complex cellular contexts are limited. Surface-enhanced Raman scattering (SERS) has emerged as a promising alternative due to its nontargeted nature and simplicity of operation. Although SERS has demonstrated its potential for detecting metabolites in biological settings, its application in deciphering metabolic interactions within multicellular systems like the TME remains underexplored. In this study, we introduce a SERS-based strategy to investigate the secreted purine metabolites of tumor cells lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor prognosis in various cancers. Our SERS analysis reveals that MTAP-deficient cancer cells selectively produce methylthioadenosine (MTA), which is taken up and metabolized by fibroblasts. Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.

2023-12-03 | GSE249082 | GEO

Methyltioadenosine regulates liver cells proteome and methylproteome. Implications in liver biology and disease.

Project description:Methylthioadenosine phosphorylase (MTAP), a key enzyme in the adenine and methionine salvage pathways, catalyzes the hydrolysis of methylthioadenosine (MTA), a compound suggested to affect pivotal cellular processes in part through the regulation of protein methylation. MTAP is expressed in a wide range of cell types and tissues and its deletion is common to cancer cells and in liver injury. The aim of this study was to investigate the proteome and methyl proteome alterations triggered by MTAP deficiency in liver cells to define novel regulatory mechanisms that may explain the pathogenic processes of liver diseases. iTRAQ analysis resulted in the identification of 216 differential proteins (p<0.05) that suggest deregulation of cellular pathways as those mediated by ERK or NFκB. R-methyl proteome analysis lead to the identification of 74 differentially methylated proteins between SK-Hep1 and SK-Hep1+ cells, including 116 new methylation sites. Restoring normal MTA levels in SK-Hep1+ cells parallels the specific methylation of 56 proteins, including KRT8, TGF and CTF8A, which provides a novel regulatory mechanism of their activity with potential implications in carcinogenesis. Inhibition of RNA binding proteins methylation is especially relevant upon accumulation of MTA. As an example, methylation of quaking protein in R242 and R256 in SK-Hep1+ cells may play a pivotal role in the regulation of its activity as indicated by the up-regulation of its target protein p27 kip1. The phenotype associated with a MTAP deficiency was further verified in the liver of MTAP+/- mice. Our data support that MTAP deficiency leads to MTA accumulation and deregulation of central cellular pathways, increasing proliferation and decreasing the susceptibility to chemotherapeutic drugs, which involves differential protein methylation.

2016-02-01 | PXD002957 | Pride

Expression Array analysis of MTAP in HT080 cells

Project description:Methylthioadenosine Phosphorylase (MTAP) is a tumor suppressor gene that encodes an enzyme responsible for the catabolism of the polyamine byproduct 5′deoxy-5′-methylthioadenosine (MTA). To elucidate the mechanism by which MTAP inhibits tumor formation, we have created isogenic MTAP+ and MTAP- HT1080 fibrosarcoma cells. In this experiment we have performed expression array analysis on MTAP-, MTAP+, and MTAP+ cells treated with the MTAP inhibitor MT-DADMe-ImmA. Three biological replicates of each sample were grown and analyzed. M- is MTAP-. M+ is MTAP+, and M+I is MTAP treated with inhibitor (48 hours).

2014-04-30 | E-GEOD-56112 | biostudies-arrayexpress

Purine synthesis inhibitor L-Alanosine impairs mitochondrial function and stemness of brain tumor initiating cells

Project description:Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygous MTAP deletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in purine salvage, we demonstrate that purine synthesis blockade via treatment with L-Alanosine (ALA), an inhibitor of de novo purine synthesis, attenuates stemness and mitochondrial function of MTAP-deficient GBM cells. Here, we use RNA-Seq with ALA-treated patient-derived GBM cells to investigate the transcriptomic impact of long-term ALA treatment.

2022-04-27 | GSE197728 | GEO

Expression Array analysis of MTAP in HT080 cells

2014-04-30 | GSE56112 | GEO

MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

Project description:Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers, however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ~10% of cancer patients with this biomarker.

2023-08-09 | GSE240145 | GEO

Tumor intrinsic PRMT5 inhibition through MTAP loss predicts response to the first-in-class type I PRMT inhibitor, GSK3368715

Project description:Type I Protein Arginine Methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginine (ADMA) residues on numerous protein substrates to modulate their activity. Type I PRMTs and many of their substrates have been implicated in human cancers, suggesting that inhibiting Type I PRMT activity offers a tractable approach for therapeutic intervention. The current report describes GSK3368715 (EPZ019997), a potent, reversible Type I PRMT inhibitor with anti-tumor activity against human cancer cells both in vitro and in vivo. GSK3368715 reduces ADMA on numerous substrates and concomitantly increases monomethyl (MMA) and symmetric dimethyl arginine (SDMA) levels. Inhibition of PRMT5, the major type II PRMT, attenuates this induction and produces synergistic antiproliferative effects in combination with GSK3368715 in cancer cells. PRMT5 activity is inhibited by 2-methylthioadenosine (MTA), a naturally occurring metabolite that accumulates in tumor cells deficient for the enzyme Methylthioadenosine Phosphorylase (MTAP). MTAP deletion in cancer cell lines correlates with sensitivity to GSK3368715, indicating a sufficient degree of PRMT5 inhibition from MTA accumulation to achieve a tumor cell-intrinsic combination. These data provide the rationale to explore MTAP status as a biomarker strategy for patient selection to maximize the anti-tumor activity of GSK3368715.

2019-08-15 | GSE126651 | GEO

The gene regulation landscape of MTAP in lung adenocarcinoma

Project description:MTAP is an enzyme and found deleted in various cancers, but its role in lung adenoacrcinoma is still unclear. This study sought to investigate the effects of MTAP on the biological behavior and global gene expression profiles in lung adenocacinoma cells. We used expression microarrays to identify the global gene alterations in lung adenocacinoma cell line, CL1-5 cells after ectopically expressing V5-tagged MTAP gene.

2022-05-12 | GSE160522 | GEO

MTAP loss promotes stemness and epigenetic reprogramming in Glioblastoma

Project description:MTAP loss promotes stemness and epigenetic reprogramming in Glioblastoma

| PRJNA533826 | ENA

Gene Array Analysis of Methylthioadenosine Supplementation in Dextran Sulfate Sodium Induced Colitis

Project description:Study hypothesized that oral supplementation of methylthioadenosine (MTA) would reduce the inflammatory response in mice exposed to an agent that induces colitis (DSS) and that this reduction in inflammatory response would lead to reduced clinical disease burden. Total RNA was collected from isolated colons of mice in the following treatment groups: untreated controls, DSS only, DSS+MTA

2011-12-20 | E-GEOD-34553 | biostudies-arrayexpress

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