Identification of YAP-TEAD gene signatures in metastatic melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA980148 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24827639.fastq.gz | Fastqsanger.gz | |||
| SRR24827640.fastq.gz | Fastqsanger.gz | |||
| SRR24827641.fastq.gz | Fastqsanger.gz | |||
| SRR24827642.fastq.gz | Fastqsanger.gz | |||
| SRR24827643.fastq.gz | Fastqsanger.gz |
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Project description:YAP1 (Yes-associated protein 1) is transcriptional co-activator that partners with the TEAD family of transcription factors to regulate gene expression. Increased YAP-TEAD activity is strongly implicated in the development, progression, and metastasis of several cancer types including melanoma, but the YAP-TEAD target genes that are responsible for YAP-TEAD-dependent melanoma progression and metastasis are largely unknown. To identify YAP-TEAD regulated genes in metastatic melanoma cells we used RNA-sequencing to compare gene expression in control A375 human melanoma cells to A375 cells expressing mutant forms of YAP with increased transcriptional activity due to the mutation of LATS inhibitory phosphorylation sites (YAPS127A or YAPS127A,S381A). To determine which YAP-dependent gene expression changes are mediated by TEADs we also included a mutant form of YAP that is unable to bind TEADS (YAPS94A,S127A).
2024-03-29 | GSE234083 | GEO
Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
2022-05-08 | PXD026872 | Pride
Project description:During placentation, placental cytotrophoblast cells differentiate into syncytiotrophoblast cells and extravillous trophoblast cells. In placenta, the expression of various genes is regulated by the Hippo pathway through the transcriptional coactivator YAP/TAZ-TEAD activity. To examine the effect of YAP/TAZ and/or TEAD on trophoblast differentiation, knockdown experiments were performed. Microarray analysis were performed to identify YAP/TAZ and/or TEAD target genes in human trophoblast.
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Project description:The genomic regulatory programs that underlie human organogenesis are poorly understood. Human pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer, and diabetes. We have now created maps of transcripts, active enhancers, and transcription factor networks in pancreatic multipotent progenitors obtained from human embryos, or derived in vitro from human embryonic stem cells. This revealed that artificial progenitors recapitulate salient transcriptional and epigenomic features of their natural counterparts. Using this resource, we show that TEAD1, a transcription factor controlled by Hippo signaling, is a core component of the combinatorial code of pancreatic progenitor enhancers. TEAD thus activates genes encoding regulators of signaling pathways and stage-specific transcription factors that are essential for normal pancreas development. Accordingly, chemical and genetic perturbations of TEAD and its coactivator YAP inhibited expression of known regulators such as FGFR2 and SOX9, and suppressed the proliferation and expansion of mouse and zebrafish pancreatic progenitors. These findings provide a resource of active enhancers and transcripts in human pancreatic multipotent progenitors, and uncover a central role of TEAD and YAP as signal-responsive regulators of the transcriptional program of early pancreas development.
2015-04-06 | E-MTAB-3061 | biostudies-arrayexpress
Project description:KRAS mutations are a predominant driver of metastatic colorectal cancer (mCRC), with approximately 10% of patients harboring the KRAS p.G12C variant. Despite the development of KRASG12C (G12Ci) and EGFR (EGFRi) inhibitors such as sotorasib and panitumumab, therapeutic resistance remains a major limitation. To define resistance mechanisms, we analyzed tissue biopsies from patients treated with G12Ci+EGFRi and employed Xenium spatial transcriptomics (Xenium ST), along with comprehensive multi-omics profiling of patient-derived xenograft (PDX) models. Known genomic alterations including NRAS p. Q61K mutations and KRASG12C amplifications were observed; however, non-genomic resistance was strongly associated with activation of the YAP-TEAD pathway. Xenium ST data revealed two key tumor subpopulations: tumor intestinal stem cells (TISCs), marked by upregulation of KRAS and YAP, and neuroendocrine-like (NE) cells, which showed KRAS upregulation alone. G12Ci+EGFRi-resistant PDX models were enriched for TISCs and associated stemness programs. The addition of a TEAD inhibitor (TEADi; IAG-933) to dual therapy induced deep tumor regression and suppressed KRAS, YAP, stemness pathways; however, NE-like cells were enriched following triple therapy. These findings suggest that TEADi enhances the efficacy of KRASG12C + EGFR inhibition by targeting TISCs but may not eliminate NE-like subpopulations, which could mediate TEAD-independent resistance and represent a therapeutic challenge.
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Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.
2020-10-30 | E-MTAB-7619 | biostudies-arrayexpress
Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.
2020-10-30 | E-MTAB-7620 | biostudies-arrayexpress
Project description:KRAS mutations are a predominant driver of metastatic colorectal cancer (mCRC), with approximately 10% of patients harboring the KRAS p.G12C variant. Despite the development of KRASG12C (G12Ci) and EGFR (EGFRi) inhibitors such as sotorasib and panitumumab, therapeutic resistance remains a major limitation. To define resistance mechanisms, we analyzed tissue biopsies from patients treated with G12Ci+EGFRi and employed Xenium spatial transcriptomics (Xenium ST), along with comprehensive multi-omics profiling of patient-derived xenograft (PDX) models. Known genomic alterations including NRAS p. Q61K mutations and KRASG12C amplifications were observed; however, non-genomic resistance was strongly associated with activation of the YAP-TEAD pathway. Xenium ST data revealed two key tumor subpopulations: tumor intestinal stem cells (TISCs), marked by upregulation of KRAS and YAP, and neuroendocrine-like (NE) cells, which showed KRAS upregulation alone. G12Ci+EGFRi-resistant PDX models were enriched for TISCs and associated stemness programs. The addition of a TEAD inhibitor (TEADi; IAG-933) to dual therapy induced deep tumor regression and suppressed KRAS, YAP, stemness pathways; however, NE-like cells were enriched following triple therapy. These findings suggest that TEADi enhances the efficacy of KRASG12C + EGFR inhibition by targeting TISCs but may not eliminate NE-like subpopulations, which could mediate TEAD-independent resistance and represent a therapeutic challenge.
2025-09-24 | GSE308699 | GEO
Project description:The prevalent understanding of Hippo signaling is one inhibitory pathway in tumor growth via deactivating the potential of YAP-TEAD transcriptional complex. The aberrant activation of YAP was observed in a series of human malignancies. However, recent studies implicate that in certain cancer types, YAP could be a tumor suppressor. Here, we reported a context-dependent function of YAP in clear cell renal carcinoma (ccRCC). Inhibition of Hippo kinase activity impeded ccRCC tumor growth and NF-κB transcriptional programs. Pharmacological blocking Hippo kinase activity or ectopic activation of YAP suppressed tumor growth in xenograft and PDX models. Mechanism studies revealed that TEAD could synchronize with P65 for NF-κB signaling activation, while YAP disrupted TEAD-NF-κB interactions and dissociated P65 from its target gene promoter, thereby inhibiting NF-κB transcriptional programs and ccRCC tumor growth. Our study identified a novel crosstalk between Hippo and NF-κB pathway, uncovered a non-canonical regulation of Hippo/YAP axis in renal cancer and suggested a novel strategy to ccRCC treatments by YAP activation.
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Project description:The Hippo tumour suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some now entering clinical trials for different cancers. Here, we investigated the cellular response to TEAD palmitoylation inhibitors, using genomic and genetic strategies. Genome-wide CRISPR/Cas9 screens revealed that mutations in genes from the Hippo, MAPK and JAK-STAT signaling pathways all modulate the cellular response to TEAD inhibition. Inhibition of TEAD palmitoylation strongly reduced YAP/TEAD target expression, whilst only mildly impacting YAP/TEAD genome binding. Additionally, expression of MAPK pathway genes was induced upon inhibition of TEAD palmitoylation, which coincided with YAP/TEAD redistribution to AP-1 transcription factor binding sites. Consistent with this, combined inhibition of TEAD and the MAPK protein MEK, synergistically blocked proliferation of several mesothelioma and lung cancer cell lines and more potently reduced the growth of patient-derived lung cancers in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.
2024-07-08 | GSE269899 | GEO