Modeling high-risk blastemal and metastatic Wilms tumors by reprogramming WiT49 cells
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ABSTRACT:
PROVIDER: PRJNA1033180 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26554513.fastq.gz | Fastqsanger.gz | |||
| SRR26554514.fastq.gz | Fastqsanger.gz | |||
| SRR26554515.fastq.gz | Fastqsanger.gz | |||
| SRR26554516.fastq.gz | Fastqsanger.gz | |||
| SRR26554517.fastq.gz | Fastqsanger.gz |
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Project description:Wilms' tumor (WT) is the most common pediatric kidney cancer with more than a 90% overall survival rate in response to standard chemotherapy. However, less-differentiated blastemal type of WT often metastasize and relapse. To remodel the high-risk WT for therapeutic intervention, we partially reprogrammed WIT49, a mixed type of WT cell line, to iPSCs, which we termed as WiT49-PRCs (Partial reprogrammed iPSCs). WiT49-PRCs express stem cell markers. When implanted into the kidney capsule in mice, WiT49-PRCs formed kidney tumors and developed both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrated that WiT49-PRC recapitulates blastema-dominant WTs. Moreover, screening FDA-approved drugs in isogeneic WiT49 and WiT49-PRC cells led to the identification of epithelial- or blastemal-dominant WT-sensitive drugs. A subset of drugs was discovered with selectivity towards blastemal WT patient derived xenografts (PDXs). HDAC inhibitors (e.g. panobinostat and romedipsin) were found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRC serves as a blastemal-dominant WT model for therapeutic intervention to improve the treatment of high-risk WT patients.
2024-11-06 | GSE246479 | GEO
Project description:The aim of the study was to identify key transcriptional regulators that might be responsible for the increased resistance to chemotherapy of blastemal Wilms tumors.
2020-04-28 | GSE98334 | GEO
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA. total samples analyzed are 16, each done as technical replicate
2015-02-18 | E-GEOD-60081 | biostudies-arrayexpress
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA.
2015-02-18 | GSE60081 | GEO
Project description:The goal of this study was to find differences in the chromatin state (active promotor regions) between two Wilms tumor subtypes (blastemal and non-blastemal).
2020-05-09 | GSE98721 | GEO
Project description:Wilms tumor (nephroblastoma) is a pediatric kidney tumor that arises from renal progenitor cells. Since the blastemal type is associated with adverse prognosis, we characterized such Wilms tumors by exome and transcriptome analysis. We detected novel, recurrent somatic mutations affecting the SIX1/2 – SALL1 pathway implicated in kidney development, the DROSHA/DGCR8 microprocessor genes as well as alterations in MYCN and TP53, the latter being strongly associated with dismal outcome. The DROSHA mutations impair the RNase III domains, while DGCR8 exhibits stereotypic E518K mutations in the RNA binding domain - both may skew miRNA representation. SIX1 and SIX2 mutations affect a single hotspot (Q177R) in the homeodomain indicative of a dominant effect. In larger cohorts, these mutations cluster in blastemal and chemotherapy-induced regressive tumors that likely derive from blastemal cells and these are characterized by generally higher SIX1/2 expression. These findings broaden the spectrum of human cancer genes and may open new avenues for stratification and therapeutic leads for Wilms tumors. 53 Wilms tumor samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays.
2015-02-18 | E-GEOD-53224 | biostudies-arrayexpress
Project description:Wilms tumor (nephroblastoma) is a pediatric kidney tumor that arises from renal progenitor cells. Since the blastemal type is associated with adverse prognosis, we characterized such Wilms tumors by exome and transcriptome analysis. We detected novel, recurrent somatic mutations affecting the SIX1/2 – SALL1 pathway implicated in kidney development, the DROSHA/DGCR8 microprocessor genes as well as alterations in MYCN and TP53, the latter being strongly associated with dismal outcome. The DROSHA mutations impair the RNase III domains, while DGCR8 exhibits stereotypic E518K mutations in the RNA binding domain - both may skew miRNA representation. SIX1 and SIX2 mutations affect a single hotspot (Q177R) in the homeodomain indicative of a dominant effect. In larger cohorts, these mutations cluster in blastemal and chemotherapy-induced regressive tumors that likely derive from blastemal cells and these are characterized by generally higher SIX1/2 expression. These findings broaden the spectrum of human cancer genes and may open new avenues for stratification and therapeutic leads for Wilms tumors.
2015-02-18 | GSE53224 | GEO
Project description:To identify underlying mechanisms involved with metastasis formation in Wilms tumors (WTs), we performed comprehensive DNA methylation and gene expression analyses of matched normal kidney (NK), WT blastemal component, and metastatic tissues (MT) from patients treated under SIOP 2001 protocol. A linear Bayesian framework model identified 497 differentially methylated positions (DMPs) between groups that discriminated NK from WT, but MT samples were divided in two groups. Accordingly, methylation variance grouped NK and three MT samples tightly together and all WT with four MT samples that showed high variability. WT were hypomethylated compared to NK, and MT had a hypermethylated pattern compared to both groups. The methylation patterns were in agreement with methylases and demethylases expression. Methylation data pointed to the existence of two groups of metastases. While hierarchical clustering analysis based on the expression of all 2569 differentially expressed genes (DEGs) discriminated WT and MT from all NK samples, the hierarchical clustering based on the expression of 44 genes with a differentially methylated region (DMR) located in their promoter region revealed two groups: one containing all NKs and three MTs and one containing all WT and four MTs. Methylation changes might be controlling expression of genes associated with WT progression. The 44 genes are candidates to be further explored as a signature for metastasis formation in WT.
2020-12-17 | GSE163372 | GEO
Project description:The goal of this study is to define biologically distinct subsets of Very Low Risk Wilms Tumors (VLRWT) using oligonucleotide arrays. Description: 52 tumors from the original case:cohort of 600 tumors from NWTS-5 met the criteria for VLRWT. Thirteen tumors were excluded for quality control reasons, resulting in 39 tumors for analysis. Global gene expression analysis was performed on these 39 tumors. A total of 4,000 probesets representing the greatest variability according to coefficient of variation was utilized for hierarchical clustering, and three clusters were identified. Two subsets within VLRWT are identified that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, this would enable future clinical stratification and broadening the definition of VLRWT. Keywords: Classification by microarray analysis
2009-12-22 | GSE14767 | GEO
Project description:Wilms tumor (WT), the commonest renal tumor of the childhood, is originated from pluripotent metanephric blastemal cells resulting in tumors with triphasic histology, composed by blastemal, epithelial, and stromal cells. Histological subtype and tumor stage have long been recognized as important prognostic factors and used for the current therapeutic approach with blastema considered as the component with the highest clinical impact. Current clinical and molecular research is directed toward identifying prognostic factors for both purposes, definition of the minimal or intense required therapy for successful treatment of children with low or high risk of relapse, respectively. In this study, to identify molecular prognostic markers predictive of tumor relapse, samples from 26 advanced (Stage III or IV) blastemal WT, whose patients presented (13 samples) or did not present (13 samples) relapse, were interrogated by 4,608 human genes immobilized in a customized cDNA platform. This analysis revealed a set of 69 differentially expressed genes, where the nine top genes were evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were technically confirmed showing down-regulation in relapse WT. TSPAN3 and NCOA6 were validated in an independent sample group. Gene trios containing these two genes combined with one of the remaining three reported a reasonable capability of discriminating relapse and no-relapse WT. Negative protein expression of MCM2 and NCOA6 was observed in around 62% and 72% of 34 independent stage III and IV WT patients, respectively without association with relapse. However, a significant association between MCM2 negative staining and chemotherapy as first treatment was observed suggesting that MCM2 protein expression is implicated anyhow with chemotherapy treatment in WT.
2011-06-01 | GSE22696 | GEO