Expression data from testicular germ cell tumor cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197347 | GEO | 2022/10/17
REPOSITORIES: GEO
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Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.
2023-03-20 | GSE216043 | GEO
Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.
2023-03-20 | GSE225852 | GEO
Project description:A greater understanding of the hypersensitivity and curability of testicular germ cell tumors (TGCTs) has the potential to inform strategies to sensitize other solid tumors to conventional chemotherapies. More than 80% of metastatic TGCT patients are cured with cisplatin-based chemotherapy. However, resistance can occur, which results in poor outcomes. The mechanisms of cisplatin hypersensitivity and resistance in these tumors and embryonal carcinoma (EC), the stem cells of TGCTs, remain largely undefined. To study the mechanisms of cisplatin acquired resistance we generated a large panel of independently derived, acquired resistant clones from three distinct parental EC models employing a protocol designed to match standard of care regimens of TGCT patients. Transcriptomics revealed highly significant alterations shared between resistant cells regardless of their parental origin. This included a highly significant enrichment of genes normally repressed by H3K27 methylation and the polycomb repressive complex 2 (PRC2) which correlated with a substantial decrease in global H3K27me3, H2AK119 ubiquitination and expression of BMI1. Importantly repression of H3K27 methylation with the EZH2 inhibitor GSK-126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSK-J4 resulted in increased cisplatin sensitivity to resistant cells. A gene signature based on H3K27me gene enrichment was associated with an increased rate of recurrent/progressive disease in testicular cancer patients. Our data indicates that repression of H3K27 methylation may be a mechanism of cisplatin acquired resistance in TGCTs and that restoration of PRC2 complex function could be a viable approach to overcome treatment failure.
2019-11-11 | GSE129696 | GEO
Project description:The emergence of cisplatin (CDDP) resistance is the main cause of treatment failure and death in patients with testicular germ cell tumors (TGCT), but its biologic background is poorly understood. To study the molecular basis of CDDP resistance in TGCT we prepared and sequenced CDDP-exposed TGCT cell lines as well as 31 primary patients’ samples. Long-term exposure to CDDP increased the CDDP resistance 10 times in the NCCIT cell line, while no major resistance was achieved in Tera-2. Development of CDDP resistance was accompanied by changes in the cell cycle (increase in G1 and decrease in S-fraction), increased number of acquired mutations, of which 3 were present within ATRX gene, as well as changes in gene expression pattern. Copy number variation analysis showed, apart from obligatory gain of 12p, several other large-scale gains (chr 1, 17, 20, 21) and losses (chr X), with additional more CNVs found in CDDP-resistant cells (e.g., further losses on chr 1, 4, 18, and gain on chr 8). In the patients’ samples, those who developed CDDP resistance and died of TGCT (2/31) showed high numbers of acquired aberrations, both SNPs and CNVs, and harbored mutations in genes potentially relevant to TGCT development (e.g., TRERF1, TFAP2C in one patient, MAP2K1 and NSD1 in another one). Among all primary tumor samples, the most commonly mutated gene was NSD1, affected in 9/31 patients. This gene encoding histone methyl transferase was also downregulated and identified among the 50 most differentially expressed genes in CDDP-resistant NCCIT cell line. Interestingly, 2/31 TGCT patients harbored mutations in the ATRX gene encoding a chromatin modifier that has been shown to have a critical function in sexual differentiation. Our research newly highlights its probable involvement also in testicular tumors. Both findings support the emerging role of altered epigenetic gene regulation in TGCT and CDDP resistance development. This submission includes complete cell lines sequencing data and processed files. The patients data are available from the authors on request.
2019-08-29 | GSE136560 | GEO
Project description:Testicular germ cell tumors (TGCTs) are hypersensitive to cisplatin-based therapy however cisplatin resistance and poor outcomes do occur in a significant number of patients. It has been suggested that a shift toward DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin resistant cell models and observed a strong association between cisplatin resistance in TGCTs cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analysis showed a strong negative correlation between gene promoter CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associate with upregulation of polycomb targets and downregulation of tumor suppressor genes. These data support the hypothesis that global remodeling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.
2020-12-25 | GSE156512 | GEO
Project description:Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15 % of patients with metastatic non-seminomas show cisplatin resistance having a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. XTT viability assay revealed strong cytotoxic impact of CDK7/ 12/ 13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild type cell lines (2102EP, NCCIT, TCam2) and the cisplatin resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines leaving the MPAF control cell line mostly unaffected. FACS based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell line specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.
2022-03-26 | GSE198248 | GEO
Project description:We used DNA content-based flow cytometry to distinguish and isolate nuclei of clonal tumor populations from primary and metastatic refractory testicular germ cell tumors (TGCTs) tissues. We then interrogated each sorted tumor populationwith whole genome aCGH and next generation sequencing (NGS). we have explored the clonal basis of refractory TGCT by investigating distinct tumor populations that were present in each tumor. Notably this included resected primary tissues and treatment refractory metastases that arose after high dose chemotherapy. These results provide new knowledge regarding the role of clonal selection and selected genomic lesions in the resistance to chemotherapy in TGCT within this exceptional cohort.
2019-02-26 | GSE123464 | GEO
Project description:Normal, premalignant and various histological subtypes of testicular germ cell tumor (TGCT) tissues were hybridized against Universal Human Reference RNA (Stratagene) onto Agilent 60mer oligo microarrays (GEO accession no GPL885). In vitro time series of two TGCT cell lines, NTERA2 and 2102Ep, treated with retinoic acid for 0, 3, and 7 days were also included. The data set (30 hybridizations) is particularly useful for comparisons between various histological subtypes of TGCT versus each other or versus normal testis. Keywords = 2102Ep Keywords = Agilent oligo microarrays Keywords = carcinoma in situ Keywords = choriocarcinoma Keywords = development Keywords = developmental biology Keywords = differenciation Keywords = embryogenesis Keywords = embryonal carcinoma Keywords = homo sapiens Keywords = human Keywords = human development Keywords = intratubular germ cell tumor Keywords = nonseminoma Keywords = NTera2 Keywords = pluripotency Keywords = pluripotent Keywords = retinoic acid Keywords = seminoma Keywords = teratocarcinoma Keywords = teratoma Keywords = testis Keywords = testicular germ cell tumor Keywords = testicular neoplasm Keywords = totipotency Keywords = totipotent Keywords = undifferentiated Keywords = universal human reference RNA (Stratagene) Keywords = yolk sac tumor Keywords: other
2005-07-01 | GSE1818 | GEO
Project description:Testicular germ cell tumors (TGCTs) are the most common tumors in young men. Fortunately, TGCTs respond very well to cisplatin -based chemotherapy and show a low incidence of acquired resistance compared to most somatic tumors. This high sensitivity also applies to more than 80% of all TGCTs with metastatic disease. The reasons for this particularly high sensitivity of male germ cell tumors to chemotherapy seem to be multifactorial. To study this phenomenon, we have addressed the issue of whether cisplatin produces germ cell tumor specific gene expression profiles using testicular germ cell tumor derived cell lines. By means of microarray technology, we have analyzed cisplatin-induced gene expression in two well characterized human testicular germ cell tumor (TGCT) derived cell lines (833K and GCT27) which are sensitive to cisplatin treatment, and in a human colon carcinoma cell line (HCT116), to compare responses in germ cell tumor cell lines with those of tumor cells of somatic origin. We further evaluate the male germ cell tumor specificity, by mining available public databases and literature. By using SAM analysis, we identified 1794 differentially expressed genes. Among these, 1180 genes were over-expressed in TGCT cells and under-expressed in HCT116 cells and 614 genes were down-regulated in TGCT cells and up-regulated in HCT116 cells after exposure to cisplatin. Functional classification of these genes showed that they participate in a variety of different and widely distributed functional categories and biochemical pathways. Keywords: Testicular germ cell tumors (TGCT) Cisplatin, Microarray, cell type comparison, Gene expression
2007-10-01 | GSE7563 | GEO
Project description:Tumor-infiltrating T cells in testicular germ cell tumors (TGCT) remain poorly understood. Therefore, along with immunohistochemistry and flow cytometry, single-cell RNA sequencing (scRNA-seq) was performed on different human TGCT testes to identify immune cell composition, with particular emphasis on delineating T cell subtypes. There are various tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells that are found in other cancer entities, but their contributions to TGCT are unknown. In this study, we found that T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. Taken together, despite significant heterogeneity between patients, this study demonstrated that T cell subtypes form a key component of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in the human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, assessing patient prognosis, and as putative targets for personalized immunotherapy.
2024-03-21 | GSE261811 | GEO