Mechanisms of cellular crosstalk in the gastric tumour microenvironment are mediated by YAP1 and STAT3
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE197002 | GEO | 2023/11/07
REPOSITORIES: GEO
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Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
2022-02-17 | GSE196672 | GEO
Project description:The Hippo signaling pathway is evolutionarily well conserved, and all core components have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador), LATS1/2 (Warts), MOB1 (Mats), YAP1/TAZ (Yorkie), and TEAD1/2/3/4 (Scalloped) (Halder and Johnson, 2011; Pan, 2007; Dong et al., 2007; Saucedo and Edgar, 2007). When Hippo signaling is active, YAP1/TAZ is phosphorylated by LATS1/2 and sequestered by 14-3-3 proteins in cytoplasm. When Hippo signaling is absent, unphosphorylated YAP1/TAZ enters the nucleus and increases transcriptional activation of genes involved in cell proliferation and survival. The indispensability of the Hippo pathway in restricting cell growth and proliferation has prompted speculation that many members of the pathway might be involved in tumorigenesis. To see the effect of YAP1 and TAZ in HCC cell, we generated gene expression profile.
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Project description:YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting.
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Project description:Hippo signaling pathway is pivotally involved in human cancer. Among the Hippo components, YAP1 is highly active while function of MST1,2 and SAV1 was lost in liver cancer. Based on systematic analysis, we identified KLF5 as YAP1 binding partner in silico. To investigate KLF5 in liver cancer, we performed the gene expression microarray after knocked down YAP1, TEAD1 and KLF5 in SK-Hep1 cell line.
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2017-05-15 | E-MTAB-4781 | biostudies-arrayexpress
Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background
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Project description:The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Its dysregulation has been well-studied to promote tumor initiation and progression, including gastric cancer (GC). Although the Hippo-YAP1 signaling pathway regulates the expression of thousands of target genes, how these target genes contribute to the oncogenic program driven by YAP1 remains unknown. Here we identified the vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Knocking down FOXP4 impairs GC spheroid formation and inhibits stemness marker expression, while its upregulation potentiates the cancer cells with more stemness. RNA-seq analysis revealed SOX12 as functional downstream of FOXP4 in the YAP1-induced carcinogenesis. Targeting FOXP4 by 42-(2-Tetrazolyl) rapamycin in GC cells enhanced the 5-FU efficacies. Our findings have unveiled FOXP4 as a novel stemness marker that promotes tumorigenesis by upregulating SOX12. Additionally, we have identified FOXP4 as a direct target for modulating YAP1 signaling in GC. Therefore, the YAP1-FOXP4-SOX12 axis presents a promising therapeutic target for GC.
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Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.
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