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PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]

ABSTRACT: PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]

PROVIDER: PRJNA1021547 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26193124_1.fastq.gz	Fastqsanger.gz
	SRR26193124_2.fastq.gz	Fastqsanger.gz
	SRR26193125_1.fastq.gz	Fastqsanger.gz
	SRR26193125_2.fastq.gz	Fastqsanger.gz
	SRR26193126_1.fastq.gz	Fastqsanger.gz

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PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq II]

Project description:The mechanisms underlying oncogenesis in desmoid-type fibromatosis are poorly understood. This project sought to understand how β-catenin may function to promote desmoid formation and how external signaling by PDGFRβ modulates this activity. To examine this question, RNA-seq was performed on CTNNB1 knock-downs. Gene set enrichment analysis suggested that the oncogene controlled HIF1 and angiogenesis pathways; expression of related genes accurately differentiated desmoids analyzed by U133A array from normal mesenchymal tissues. We identified c-ABL as a direct transcriptional target of β-catenin that promoted HIF1α expression in desmoid cells. We also noted that c-ABL activity was enhanced by PDGFRβ. PDGFRβ enhanced desmoid cell proliferation and c-ABL was necessary for desmoid proliferation. To identify potential markers of PDGFRβ/c-ABL activity in vivo, we assessed RNA-seq of desmoid cells treated with PDGF-BB. ERG1 transcription was highly upregulate and IHC of ERG1 was subsequently used to assess outcomes in desmoid patients with biopsies available for testing.

2023-11-01 | GSE239407 | GEO

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq I]

2023-11-01 | GSE239406 | GEO

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [ChIP-seq]

Project description:Purpose: This study sought to identify signaling pathways that modulate β-catenin function in desmoid cells, affecting natural history and sorafenib response. Experimental Design: In vitro experiments utilized primary desmoid cell lines to examine interaction of β-catenin signaling with other pathways. Relevance of in vitro results was assessed in surgical specimens and Alliance trial A091105 correlative biopsies. Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α. Expression of hypoxia-associated genes clustered desmoids separately from normal mesenchymal tissue. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α protein expression and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1 inhibited the ability of desmoid cells to induce VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by activation of PDGF signaling. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in samples from patients after treatment with sorafenib; baseline samples in patients with greater drug response tended to have higher baseline PDGFRβ/c-Abl pathway activation. Conclusions: The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α protein expression in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

2023-11-01 | GSE244160 | GEO

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [microarray]

Project description:Unsupervised clustering of desmoid tumors and normal mesenchymal tissues was performed using henes associated with HIF1 activity. This accurately distiguished neoplastic tissues from normal controls The study sought to identify genes differentially expressed in desmoid-type fibromatosis as opposed to normal mesenchymal tissues. We noted that beta-catenin, the central driver in desmoid-type fibromatosis, appeared to regulate HIF1 signaling in in vitro studies. Genes associated with HIF1 and angiogenesis pathways were then used to perform unsupervised clustering on desmoid tumors and normal mesenchymal tissues. The genes accurately differentiated neoplastic and normal samples.

2023-10-31 | GSE237692 | GEO

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis

Project description:PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis

| PRJNA999217 | ENA

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [microarray]

Project description:PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [microarray]

| PRJNA996168 | ENA

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq I]

Project description:PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq I]

| PRJNA999228 | ENA

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq II]

Project description:PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis [RNA-seq II]

| PRJNA999230 | ENA

PDGFRβ Signaling Cooperates with β-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis.

Project description:PurposeThis study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.Experimental designIn vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.ResultsCTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.ConclusionsThe β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

| S-EPMC10792363 | biostudies-literature

PDGFRβ signaling cooperates with β-catenin to modulate c-Abl and biologic behavior of desmoid-type fibromatosis

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-01 | GSE239409 | GEO