MTAP loss promotes stemness and epigenetic reprogramming in Glioblastoma
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ABSTRACT:
PROVIDER: PRJNA533826 | ENA |
REPOSITORIES: ENA
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Project description:Methylthioadenosine Phosphorylase (MTAP) loss is one of the most frequent genetic alterations in Glioblastoma and has been associated with poor clinical outcomes in several cancer types. Here we used patient derived glioblastoma cell lines and manipulated MTAP status to create isogenic pairs with which to study the effects of this alteration on epigenetics, gene expression, and cell identity
2019-11-01 | GSE130093 | GEO
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
Project description:Abstract The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis, and patients with low MTAP expression displayed worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduced the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. Vimentin was revealed as a novel dimethyl-protein with less dimethylation level in response to MTAP loss. The sDMA modification on vimentin reduces its protein abundance and trivially affects its filamentous structure. In MTAP-loss cells, lower sDMA level prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin, contributing to cell invasion. This inverse association of the MTAP/PRMT5 axis with vimentin proteins was clinically corroborated. Taken together, we propose a novel mechanism of vimentin post-translational regulation and provide new insights in metastasis.
2022-05-31 | PXD031192 | Pride
Project description:Background: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer. Methods: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Results: transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. Conclusion: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.
2025-09-05 | GSE276571 | GEO
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
Project description: Not available
| S-EPMC6810595 | biostudies-literature
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.
2014-04-30 | GSE56112 | GEO
Project description: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
2020-05-12 | GSE114867 | GEO
Project description:By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modelling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the “energy barriers” separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish for the first time the concept of oncometabolic nuclear reprogramming of stemness as a novel metabolo-epigenetic mechanism for generation of cancer stem-like cells.
2016-04-08 | GSE76263 | GEO
Project description: Not available
| S-EPMC9791736 | biostudies-literature