Temporal activation of WNT/ β-catenin signaling is sufficient to inhibit SOX10 expression and block melanoma growth
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ABSTRACT:
PROVIDER: PRJNA610538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11243568.fastq.gz | Fastqsanger.gz | |||
| SRR11243569.fastq.gz | Fastqsanger.gz | |||
| SRR11243570.fastq.gz | Fastqsanger.gz | |||
| SRR11243571.fastq.gz | Fastqsanger.gz | |||
| SRR11243572.fastq.gz | Fastqsanger.gz |
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Project description:Despite advances in the systemic treatment of patients with metastatic melanoma using immune checkpoint and tyrosine kinase inhibitors (TKI), the majority of stage IV melanoma patients eventually succumb to the disease. We have previously identified the transcription factor Sox10 as a crucial player in melanoma, yet the underlying molecular mechanisms mediating Sox10-dependent tumorigenesis remain largely uncharacterized. Here, we show that MEK and RAF inhibitors do not suppress SOX10 expression in patient-derived cells in vitro, as well as in melanoma patients in vivo. In a search for pharmacological inhibitors of SOX10, we performed a mass spectrometry-based screen in human melanoma cells. Subsequent analysis revealed that SOX10 directly interacts with b-catenin, which is a key mediator of canonical Wnt/b-catenin signaling. We demonstrate that inhibitors of glycogen synthase kinase 3 alpha/beta (GSK3α/b) efficiently abrogate SOX10 expression in human melanoma cells in vitro and in melanoma mouse models in vivo. The mechanism of action of GSK3-mediated SOX10 suppression is transcription-independent and relies on the presence of a proteasome degradable form of b-catenin. Taken together, we provide evidence that activation of canonical Wnt signaling has a profound effect on melanoma growth and is able to counteract Sox10-dependent melanoma maintenance both in vitro and in vivo
2021-01-01 | GSE146415 | GEO
Project description:Despite advances in the systemic treatment of patients with metastatic melanoma using immune checkpoint and tyrosine kinase inhibitors (TKI), the majority of stage IV melanoma patients eventually succumb to the disease. We have previously identified the transcription factor Sox10 as a crucial player in melanoma, yet the underlying molecular mechanisms mediating Sox10-dependent tumorigenesis remain largely uncharacterized. Here, we show that MEK and RAF inhibitors do not suppress levels of SOX10 protein in patient-derived cells in vitro, as well as in melanoma patients in vivo. In a search for pharmacological inhibitors of SOX10, we performed a mass spectrometry-based screen in human melanoma cells. Subsequent analysis revealed that SOX10 directly interacts with β-catenin, which is a key mediator of canonical Wnt/β-catenin signaling. We demonstrate that inhibitors of glycogen synthase kinase 3 alpha/beta (GSK3α/β) efficiently abrogate SOX10 protein in human melanoma cells in vitro and in melanoma mouse models in vivo. The mechanism of action of GSK3-mediated SOX10 suppression is transcription-independent and relies on the presence of a proteasome degradable form of β-catenin. Taken together, we provide evidence that activation of canonical Wnt signaling has a profound effect on melanoma growth and is able to counteract Sox10-dependent melanoma maintenance both in vitro and in vivo.
| S-EPMC8076051 | biostudies-literature
Project description:Sensorineural deafness can occur in campomelic dysplasia (CD). In a mouse model of the SOX9Y440X/+ CD mutation, SOX10 downregulation was previously shown to be associated with impaired development of the endolymphatic system at mid-gestation. The underlying molecular causes are unknown. Here we found at E10.5 when the otocyst lacks overt inner ear structures, Sox10 was downregulated in the dorsal and medial aspects of the Sox9Y440X/+ otic epithelium, regions associated with specification of the endolymphatic sac and duct. Single-cell transcriptomic profiling revealed differential elevation of Wnt signaling pathway genes associated with the domain-specific Sox10 reduction. Otocyst-specific forced elevation of Wnt signaling by expression of stabilized β-catenin suppressed Sox10 expression. Similarly, WNT exerted an inhibitory effect on SOX10 expression in human inner ear organoids derived from pluripotent stem cells. We propose a conserved regulatory model of SOX9-WNT antagonism governing SOX10 action in the otocyst underlies the specification of endolymphatic cell fate, with important implications for understanding human deafness syndromes.
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Project description:Given the heterogeneous expression of SOX10 in naïve melanoma, we sought to characterize SOX10 deficient population. To this end, we generated SOX10 CRISPR/Cas9 knockouts using two different guide RNAs (gRNA, #2 and #4) in the A375 (BRAF mutant) metastatic cell line. Using this approach, we identified multiple clones with loss of SOX10 expression. RNA-seq was performed to characterize the SOX10-regulated transcriptome. We used GSEA analysis to evaluate significant pathway changes in SOX10 knockout cells when compared to parental cells. We observed an enrichment in pathways associated with the tumor microenvironment (epithelial-mesenchymal transition; TGF beta signaling; extracellular structure organization; apical junction; hypoxia; angiogenesis), alterations in metabolic pathways (increase in the glycolysis pathway), a reduction in MYC and E2F targets and upregulation in p53 pathway and TNFA signaling via NFkB in the SOX10 knockout cells compared to parental cells. SOX10 negative clones have been identified in the minimal residual disease in BRAF mutant PDX models following BRAF and MEK inhibition and in patient samples while on treatment and SOX10 loss has been described as a resistant mechanism in BRAF mutant melanoma patients following vemurafenib treatment. Thus, we also analyzed the transcriptome profile of SOX10 low/deficient cells that arose following BRAFi+MEKi treatment in vivo. We performed GSEA analysis on RNA-seq data of CRT34 and CRT35 cells compared to parental A375 cells. CRT34 and CRT35 showed a very similar transcriptome profile to SOX10 KO cells when compared to A375 parental cells
2022-01-24 | GSE180568 | GEO
Project description:We have shown that Sox10 plays a crucial role in the initiation and maintenance of giant congenital nevi and melanoma in a mouse model of melanoma.To dissect the molecular mechanisms and analyze the role of SOX10 in the maintenance of human melanoma, we have performed microarray study. Human melanoma cell line M010817 was transfected with either control shRNA or SOX10 shRNA. RNA was isolated at 48 hours and 96 hours after transfection and subjected to hybridization on Affymetrix microarrays.
2012-07-02 | E-GEOD-37059 | biostudies-arrayexpress
Project description:The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF-family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium using tissue-specific, inducible beta-catenin gene ablation in adult mice. Block of Wnt/beta-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of beta-catenin resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture micro dissection confirmed those observations and allowed to identify genes potentially responsible for the functional preservation of intestinal stem cells. Experiment Overall Design: laser capture microdissection of intestinal crypts, control vs. beta-catenin mutant (2days after induction of deletion by tamoxifen), two rounds of amplification of mRNA
2008-06-16 | E-GEOD-8818 | biostudies-arrayexpress
Project description:It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNA specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 are likely to be involved in migration and metastasis of melanoma cells. We carried out microarray-based gene expression profiling using Sox10-specific siRNA to identify regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1R) partake in the regulation of migration. We provide evidences that a significant portion of the effect of Sox10 on migration is mediated by Mitf, a transcription factor downstream to Sox10. The involvement of Mc1R in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represent potential targets of therapeutic intervention. Chemically synthesized siRNA duplex (WT1-Sox10) was used to knock-down the transcription factor Sox10 in murine melanoma cell line B16F10. For the control, siRNA containing 5 nucleotide alterations (MT1-Sox10) were used. Total RNA was subsequently prepared to synthesize probes for microarray screening. A total of three pairs of replicate samples were generated each from separate transfection followed by RNA preparation. Expression values were determined and compared within each pair of WT1-Sox10 and MT1-Sox10 transfections. Genes showing over 2 fold changes in all three replicate pairs were subjected to subsequent analyses.
2010-11-20 | E-GEOD-25501 | biostudies-arrayexpress
Project description:Domestic rock pigeons (Columba livia) homozygous for either of two “recessive red” mutations, which are partially-overlapping deletions causing downregulation of Sox10, display brilliant red colors instead of blue/black feathers. Sox10 encodes a transcription factor important for melanocyte differentiation and function, but the precise role that it plays in promoting eumelanin over pheomelanin pigment production in pigeons are unknown. In this study, we perform ChIPseq for SOX10, H3K27ac, and H3K27me3 to better understand the genome occupancy of SOX10 in avian melanocytes.
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Project description:ChIP-seq of Sox10 in spinal cord and sciatic nerve 2 independent Sox10 ChIP samples each for spinal cord (CNS) and sciatic nerve (PNS), with respective inputs
2015-04-01 | E-GEOD-64703 | biostudies-arrayexpress
Project description:Stabilized Alpha-Helix peptides of BCL9 HD2 (SAH-BCL9) block BCL9 and B9L interactions with beta-catenin and specifically downregulate Wnt target gene expression.
2012-08-23 | GSE33143 | GEO