Cadherin-11 contributes to the heterogenous and dynamic Wnt-Wnt-β-catenin pathway activation in Ewing sarcoma
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ABSTRACT:
PROVIDER: PRJNA1098647 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28616326_1.fastq.gz | Fastqsanger.gz | |||
| SRR28616326_2.fastq.gz | Fastqsanger.gz | |||
| SRR28616327_1.fastq.gz | Fastqsanger.gz | |||
| SRR28616327_2.fastq.gz | Fastqsanger.gz | |||
| SRR28616328_1.fastq.gz | Fastqsanger.gz |
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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | Pride
Project description:Ewing sarcoma (ES) is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis. ES tumors are driven by the fusion gene EWS/Fli1, and while these tumor are genetically homogenous, the transcriptional heterogeneity can lead to a variety of cellular processes including metastasis. In this study, we demonstrate that in ES cells, the canonical Wnt/-Catenin signaling pathway is heterogeneously activated in vitro and in vivo, correlating with hypoxia and EWS/Fli1 activity.
2025-04-21 | GSE263651 | GEO
Project description:Wnt/beta-catenin signaling is active in small subpopulations of Ewing sarcoma cells and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these beta-catenin-activated Ewing cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell autonomous mechanisms, Wnt/beta-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of pro-angiogenic ECM proteins, collectively termed the angiomatrix. Here we tested the role of Wnt-related TGF-beta signaling in angiomatrix induction by obtaining mRNA from Wnt3a-treated TC32 cells in the presence and absence of SB505124, a chemical inhibitor of TGF-beta receptor 1 (TGFBR1) and subjecting it to short read RNA-sequencing.
2020-06-23 | GSE124523 | GEO
Project description:Ewing sarcomas are characterized by the presence of EWS/ETS fusion genes in the absence of other recurrent genetic alterations and mechanisms of tumor heterogeneity that contribute to disease progression remain unclear. Mutations in the Wnt/beta-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis. We evaluated beta-catenin and LGR5 expression in Ewing sarcoma cell lines and tumors and noted marked intra- and inter-tumor heterogeneity. Tumors with evidence of active Wnt/beta-catenin signaling were associated with increased incidence of tumor relapse and worse overall survival. Paradoxically, RNA sequencing revealed a marked antagonism of EWS/ETS transcriptional activity in Wnt/beta-catenin activated tumor cells. Consistent with this, Wnt/beta-catenin activated cells displayed a phenotype that was reminiscent of Ewing sarcoma cells with partial EWS/ETS loss of function. Specifically, activation of Wnt/beta-catenin induced alterations to the actin cytoskeleton, acquisition of a migratory phenotype and up regulation of EWS/ETS-repressed genes. Notably, activation of Wnt/beta-catenin signaling led to marked induction of tenascin C (TNC), an established promoter of cancer metastasis, and an EWS/ETS-repressed target gene. Loss of TNC function in Ewing sarcoma cells profoundly inhibited their migratory and metastatic potential. Our studies reveal that heterogeneous activation of Wnt/beta-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing sarcoma. Significantly, this is mediated, at least in part, by inhibition of EWS/ETS fusion protein function that results in de-repression of metastasis-associated gene programs.
2016-11-30 | GSE75859 | GEO
Project description:Wnt/beta-catenin activated Ewing sarcoma cells promote the angiogenic switch
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Project description:The aggregation of nephron progenitor cells (NPC) is required to form the nephron precursor renal vesicle (RV) as they undergo the mesenchymal-to-epithelial transition (MET). Canonical Wnt signaling regulates the MET of NPCs via the effector molecule β-catenin. β-catenin acts as a transcriptional co-activator during the differentiation of NPCs, however, if it has any role as an adhesion regulating molecule via the cadherin-catenin complex is currently unknown. Using in vitro NPC culture system with gene editing and modulated Wnt signaling input, we investigated the morphological transition of NPCs and its underlying mechanism modeling the initial step of the MET in vivo. Increasing Wnt signaling input with the small molecule agonist CHIR resulted in the aggregation of NPCs similar to the generation of the nephron anlagen. By removing β- and α-catenin from the NPCs, NPCs are sorted out from these aggregates, demonstrating the key role of the cadherin-catenin complex in the aggregation. β-catenin was essential for the induction, however, the removal of α-catenin did not affect the transcriptional profile of NPCs. Removal of extracellular Ca2+ resulted in the transient loss of cell-cell contacts suggesting the role of cadherins in the aggregation process. The analysis of in vitro bulk RNA-seq cadherin expression profile matched the in vivo cadherin expression profile determined by single-cell RNA-seq. The combined removal of pre-existing and inducible cadherins phenocopied the results of β- and α-catenin KO experiments highlighting the crucial role of the cadherin-catenin complex by multiple lines of evidence. Notably, the induction of NPCs is independent of their aggregation. The in vitro modeling of nephron development provides a mechanistic understanding how cell adhesion is regulated via the cadherin-catenin complex during nephrogenesis.
2024-07-29 | GSE232606 | GEO
Project description:Canonical Wnt signaling is crucial for vascularization of the central nervous system and blood-brain barrier (BBB) formation. BBB formation and modulation are not only important for development, but also relevant for vascular and neurodegenerative diseases. However, beyond the early requirement of Wnt signaling for brain capillary development, there is little understanding of how Wnt signaling further contributes to brain angiogenesis and BBB formation. By combining high resolution in vivo imaging with temporally and spatially controlled manipulation of Wnt signaling, we were able to dissect different requirements for Wnt signaling during brain angiogenesis and BBB formation. In the absence of Wnt signaling, premature Sphingosine-1-phosphate receptor (S1pr) signaling leads to a reduction of VE-cadherin and Esama at cell-cell junctions. Wnt signaling most likely suppresses S1pr signaling during angiogenesis to enable the dynamic junction formation during anastomosis, whereas later S1pr signaling regulates BBB maturation and VE-cadherin stabilization. Our data provides a novel link between brain capillary angiogenesis and BBB formation and identifies Wnt signaling as coordinator of the timing and as regulator of anastomosis.
2018-10-12 | GSE121041 | GEO
Project description:The Wnt/β-catenin signaling pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the context-specific outcome of Wnt signaling is determined by the collaborative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. The contribution of FOX transcription factors to Wnt signaling has not been investigated in a systemic manner. Here, by combining β-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected FOX family members, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity and the expression of Wnt ligands and target genes. We conclude that FOX proteins are common regulators of the Wnt/β-catenin pathway that may control the outcome of Wnt signaling in a tissue-specific manner.
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Project description:The epithelial-mesenchymal transition (EMT) is closely linked to the acquisition of cancer stem cell (CSC) properties, which contribute to treatment resistance and metastasis. This study investigates the role of the E3 ubiquitin-ligase Hakai, the first identified post-translational regulator of E-cadherin stability, in promoting CSC traits in colorectal cancer (CRC). To examine Hakai’s involvement in CSC regulation, we used an inducible shRNA in a HT29 cells. Under conditions that promote CSC characteristics, we silenced Hakai and evaluated tumoursphere formation and CSC marker expression. Proteomic and bioinformatic analyses were performed to identify Hakai-regulated proteins in tumoursphere cultures. Additionally, Western blot, RT-qPCR, co-immunoprecipitation, immunofluorescence and TOPFlash assays were employed to study CSC-related protein regulation in response to Hakai expression. Furthermore, we assessed the impact of Hakin-1, the pharmacological inhibitor specifically targeting Hakai’s HYB domain responsible for its E3 ubiquitin-ligase activity, on tumoursphere properties. Hakai silencing significantly reduced tumoursphere size and number accompanied by decreased expression of CSC markers and Wnt target genes. CSC-related proteins regulated by Hakai were identified, including LRP4, a negative regulator of Wnt/β-catenin pathway. Hakai interacts with LRP4, promoting its ubiquitination and degradation. Moreover, Hakai overexpression induces hyperactivation of Wnt/β-catenin sand disrupts LRP4’s inhibitory effect. Treatment with Hakin-1 effectively inhibited self-renewal and promoted differentiation within tumourspheres. These findings suggest that Hakai promotes CSCs properties by hyperactivation of the Wnt/β-catenin pathway via LRP4-mediated modulation. Additionally, Hakin-1 emerges as a promising therapeutic agent targeting CSCs by enhancing differentiation and attenuating Wnt/β-catenin activity, highlighting Hakai as a potential target for improving CSC treatment.
2026-06-22 | PXD069248 | Pride
Project description:Beta-catenin is an essential mediator of canonical Wnt signaling and a central component of the cadherin-catenin epithelial adhesion complex. Dysregulation of beta-catenin expression has been described in pancreatic neoplasia. Newly published studies have suggested that beta-catenin is critical for normal pancreatic development although these reports reached somewhat different conclusions. In addition, the molecular mechanisms by which loss of beta-catenin affects pancreas development are not well understood. The goals of this study then were; 1] to further investigate the role of beta-catenin in pancreatic development using a conditional knockout approach and 2] to identify possible mechanisms by which loss of beta-catenin disrupts pancreatic development. A Pdx1-cre mouse line was used to delete a floxed beta-catenin allele specifically in the developing pancreas, and embryonic pancreata were studied by immunohistochemistry and microarray analysis. Experiment Overall Design: Parameter: embryonic pancreas from wild type and Pdx1Cre/+; beta-cateninflox/flox Experiment Overall Design: Sample type: RNA Experiment Overall Design: Source name: Embryonic day 14.6 and 16.5 pancreas Experiment Overall Design: Organism: Mus Musculus Experiment Overall Design: Strain: Derived from an intercross of Pdx1Cre/+ ; beta-cateninflox/+ mice. Experiment Overall Design: Extracted molecule:Total RNA Experiment Overall Design: In the study, we hybridized RNA from Embryonic day 14.6 and 16.5 pancreas of wild type (WT) control and Pdx1Cre/+; beta-cateninflox/flox beta-catenin null in the pancreas) embryonic pancreas to Affymetrix MOE430 2.0 GeneChip® arrays containing 45,101 well characterized mouse genes/ESTs.
2007-12-13 | E-GEOD-7430 | biostudies-arrayexpress