Transcriptional profiling of Wilms tumor via single nuclei RNA sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE296618 | GEO | 2025/06/01
REPOSITORIES: GEO
Similar Datasets
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 is the most common kidney cancer in children, and anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how anaplastic Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal biogenesis. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Accordingly, increased proteasome levels are associated with anaplastic histology and with worse prognosis in Wilms tumor. Lastly, we show that the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment both in vitro and in vivo.
2024-06-20 | GSE270330 | 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.
2015-02-18 | GSE53224 | GEO
Project description:The lack of model systems limits the preclinical testing of novel therapies to address Wilms tumor patient groups with poor outcomes. Therefore, we established 45 heterotopic Wilms tumor patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). These WTPDX include six showing diffuse anaplasia, nine from patients who went on to experience disease relapse, and thirteen from patients with bilateral disease. WTPDX retained the genetic alterations and the global transcriptomic and methylation profile of corresponding primary WT. In addition, favorable histology WTPDX were chemosensitive, while unfavorable histology WTPDX were resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool for the testing of novel targeted therapies in the era of precision medicine.
2019-02-14 | GSE110697 | GEO
Project description:The lack of model systems limits the preclinical testing of novel therapies to address Wilms tumor patient groups with poor outcomes. Therefore, we established 45 heterotopic Wilms tumor patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). These WTPDX include six showing diffuse anaplasia, nine from patients who went on to experience disease relapse, and thirteen from patients with bilateral disease. WTPDX retained the genetic alterations and the global transcriptomic and methylation profile of corresponding primary WT. In addition, favorable histology WTPDX were chemosensitive, while unfavorable histology WTPDX were resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool for the testing of novel targeted therapies in the era of precision medicine.
2019-02-14 | GSE110696 | GEO
Project description:Recently the cancer stem cell (CSC) model has been put forward to describe how a subset of cells within the tumor is responsible for tumor growth and heterogeneity. Wilms' tumor (WT), the most common pediatric renal malignancy, arises from developmentally arrested early renal progenitors. WT NCAM1+ALDH1+ CSCs have been recently isolated and shown to localize to tumor blastema. Herein by generating 'blastema'-only WT xenografts composed solely by cells expressing the SIX2 and NCAM1 embryonic renal stem cell markers, we surprisingly show that sorted ALDH1+ WT CSCs are phenotypically not the earliest renal stem cells. Rather, gene expression and proteomic comparative analysis disclose a more differentiated self-renewing epithelial cell type than bulk of the blastema. Thus, WT CSCs do not represent the transformed counterpart of the most primitive renal stem cell being more differentiated than the presumable WT cell of origin and are likely to de-differentiate to propagate the tumor blastema. We used Wilms tumor Xns, as well as, fetal renal tissue originally obtained from a patients or aborted fetus
2015-12-31 | E-GEOD-57269 | biostudies-arrayexpress
Project description:Purpose: The 10x Genomics Visium platform allows us to define the spatial topography of gene expression and provides detailed molecular maps that overcome limitations associated with sn/scRNA-seq and microscopy-based spatial transcriptomics methods. The goals of this study are to compare and identify unique transcriptome profiling (RNA-seq) signature between unfavorable and favorable Wilms Tumors and against human fetal kidney. Methods: Human fetal kidney and Wilms tumor spatial topography of gene expression were generated using the 10X Visium platform Results: Using an optimized data analysis workflow, we mapped the reads to the hg38 genome build and grouped the spots into 9 clusters based on gene expression profiles. Conclusion: Our study represents the first implement of Visium technology in human fetal kidney and Wilms Tumor tissue, providing a number of important functional insights about the spatial and molecular definitions of cell populations across human fetal kidney and different subtypes of Wilms Tumor through analyzing gene expression within the intact spatial organization of the human samples.
2023-07-01 | GSE178349 | GEO
Project description:Precise regulation of transduction signaling pathways genes is crucial for correct differentiation of kidney cells and perturbation may lead to tumor onset. Wilms tumors (WT), or nephroblastoma, originates from the metanephric blastema cells, which were unable to complete the differentiation, resulting in a triphasic tumor composed by distinct cell types, blastemal, epithelial and stromal, where the former harbor molecular characteristics similar to cells of the earliest stages of kidney development. In this study, to identify key early events involved in the disruption of correct cell signaling during kidney differentiation that can drive WT, we developed a cDNA platform containing genes from signaling transduction pathways. By using bioinformatics tools, we defined high conserved regions between human and mouse orthologous genes and assessed the gene modulation in blastemal cells captured from WT and differentiated kidneys (DK) in human and from four temporal stages of kidney differentiation in mouse. We found 18 genes, whose transcriptional level of the earliest phases of blastemal cell differentiation was recapitulated in WT. PAX2, FZD10, SHPK, WNT5B, FZD2, CRABP2, FRZB, GRK7, TESK1, HDGF and IGF2 were up- and MAPK9, PIK3CA, FRAT2, ITPR3, CDH6, HIPK1 and TIMP3 were down-regulated in WT respectively. Hierarchical clustering based on the expression of this gene set grouped DK from both species, human and mouse, and discriminated them from fetal kidney and WT in human, and the earliest kidney stages in mouse, validating the model proposed by this study and reveling a transduction signaling signature of WT. High robustness of this data was detected since expression level was tested by quantitative RT-PCR in the initial and independent sample set, with 75 and 56% of agreement. Agreement of 62% was also observed in protein level assessing blastemal component of an independent group of 137 WT. Protein expression of CRABP2, IGF2, GRK7, TESK1, HDGF, WNT5B, FZD2 and TIMP3 was also characterized in human fetal kidneys revealing interesting aspects of kidney differentiation. This study identified key genes modulated during kidney differentiation which may play a determinant role for WT onset. As far as we know, FZD10, FRZB, HDGF, MAPK9, FRAT2, SHPK, WNT5B, GRK7, TESK1, HDGF, PIK3CA, ITPR3, HIPK1 and TIMP3 were not previously associated to WT. The strong connection between nephrogenesis and WT highlights the importance of a detailed characterization of modulated genes belonged to signal transduction. Identification of gene expression involved in kidney differentiation arresting might be imperative to point out early alterations that drive WT onset and consequently are potential candidate as molecular marker. Here, we characterized expression pattern of genes belonged to transduction signaling pathways in blastemal cells during kidney development stages in mouse and WT in human. For that, we established a model of inter- and intra-specific hybridization to assess gene expression modulation to identify key events that drive WT onset. Dye-swap was performed for each sample as control for dye bias and used as replicate. In total, 24 frozen favorable histology WT and differentiated kidney samples were laser microdisscted for blastemal cells. Three kidneys from CD1 lineage from Mus Musculus were isolated from embryos (E) and postnatal animals (P) at ages E15.5, E17.5, P1.5 and P7.5 for laser microdissection of the blastemal cells in all stages of kidney differentiation. NA were purified with PicoPure™ RNA Isolation kit (Arcturus Engineering #KT0204) and treated with RNase-Free DNase Set (Qiagen #79254; Qiagen-Germantown MD USA).
2011-12-07 | E-GEOD-25965 | 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. total samples analyzed are 16, each done as technical replicate
2015-02-18 | E-GEOD-60081 | biostudies-arrayexpress