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Novel targeting of DNA methyltransferase activity inhibits Ewing sarcoma cell proliferation and enhances tumor cell sensitivity to DNA damaging drugs by activating the DNA damage response

ABSTRACT: Genome wide epigenomic analysis of Ewing Sarcoma human cell lines treated with 5AzadC and MC3343. Samples included 9 x TC-71, 9 x A673 samples, and 8 x PDX samples. For each cell line and condition ( 5AzadC, MC3343, Contol), we created 3 replicates, except PDX with 5AzadC treatment for which only 2 samples were created.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202143 | GEO | 2022/06/01

REPOSITORIES: GEO

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Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response.

Project description:DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.

| S-EPMC9197596 | biostudies-literature

The effect of STAG2 loss in Ewing sarcoma

Project description:SMC1a HiChIP was performed for the Ewing sarcoma cell line A673 under two conditions: 1) cells treated with non-targeting CRISPR Cas9 guides or 2) STAG2-targeting CRISPR Cas9 guides. Cells treated for gene editing were clonally selected and confirmed to either express STAG2 (control condition) or have loss of STAG2 expression (STAG2 loss condition). For the control condition, we used the cell clones A673.sgNT-1c4 and the STAG2 knockout clone A673.sgSTAG2-1c6. HiChIP was performed for each clone in duplicate.

2021-05-14 | GSE113100 | GEO

KSDM1b Role in Ewing Sarcoma

Project description:This study looks at the transcriptional profile of LSD2 knockdown in A673 Ewing sarcoma cells.

2019-08-29 | GSE126275 | GEO

Human A673 Ewing sarcoma secretome - effect of EWS-FLI-1 silencing

Project description:EWS-FLI-1 was silenced by an shRNA in A673 Ewing sarcoma cells and the resulting alterations in the secretome was analyzed by GeLC-MS/MS approach (six gel slices for each sample, luciferase shRNA-expressing cell secretome as control)

2021-07-06 | PXD016052 | Pride

Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy

Project description:We evaluated the miRNA content of CD99pos EXOs isolated from the parental cell line TC-71 (three samples) and of CD99neg EXOs isolated from TC-CD99-shRNA cells (four samples) by microarray analysis.

2019-07-01 | E-MTAB-7585 | biostudies-arrayexpress

MicroRNAs and DNA-Damaging Drugs in Breast Cancer: Strength in Numbers.

Project description:MicroRNAs are a class of small non-coding regulatory RNAs playing key roles in cancer. Breast cancer is the most common female malignancy worldwide and is categorized into four molecular subtypes: luminal A and B, HER2+ and triple-negative breast cancer (TNBC). Despite the development of multiple targeted therapies for luminal and HER2+ breast tumors, TNBC lacks specific therapeutic approaches, thus they are treated mainly with radio- and chemotherapy. The effectiveness of these therapeutic regimens is based on their ability to induce DNA damage, which is differentially resolved and repaired by normal vs. cancer cells. Recently, drugs directly targeting DNA repair mechanisms, such as PARP inhibitors, have emerged as attractive candidates for the future molecular targeted-therapy in breast cancer. These compounds prevent cancer cells to appropriate repair DNA double strand breaks and induce a phenomenon called synthetic lethality, that results from the concurrent inhibition of PARP and the absence of functional BRCA genes which prompt cell death. MicroRNAs are relevant players in most of the biological processes including DNA damage repair mechanisms. Consistently, the downregulation of DNA repair genes by miRNAs have been probe to improve the therapeutic effect of genotoxic drugs. In this review, we discuss how microRNAs can sensitize cancer cells to DNA-damaging drugs, through the regulation of DNA repair genes, and examine the most recent findings on their possible use as a therapeutic tools of treatment response in breast cancer.

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Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs.

Project description:Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical Cmax, if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation.SignificanceClinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

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Establishment and characterization of testicular cancer patient-derived xenograft (PDX) models [RNA-seq]

Project description:Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages.

2020-07-29 | GSE152270 | GEO

Establishment and characterization of testicular cancer patient-derived xenograft (PDX) models [SNP array]

2020-07-29 | GSE155262 | GEO

Ewing sarcoma compared to a normal body map

Project description:Primary pediatric Ewing sarcoma (ES), one uncharacterized sarcoma as well as primary and well established ES cell lines were compared to probes of different normal tissues 8 Ewing sarcoma patient samples (MuET-x), 3 primary ES cell lines (SB-KMS-y), 3 well established ES cell lines (A673, SK-N-MC, RD-ES) and 22 normal tissues (PBMC, spleen, thymus, stomach, ...., uterus, fetal brain, fetal liver) were analyzed.

2013-05-01 | E-GEOD-45544 | biostudies-arrayexpress

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