Conditional expression of sh-YAP1 modulates YAP1/TEAD-dependent transcription and causes regression of established human malignant mesothelioma MSTO-211H [sh-YAP1] xenografts.
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PROVIDER: PRJNA806795 | ENA |
REPOSITORIES: ENA
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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: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, expression of a dominant negative TEAD2 modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, TEAD2 activity is essential to maintain the growth of mesothelioma tumors in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
2022-02-17 | GSE196691 | GEO
Project description:YAP is the principle effector of the Hippo signaling pathway; a key regulator of tissue homeostasis whose dysregulation is linked to cancer development. YAP regulation of gene expression is thought to involve the TEAD transcription factor family. Here we show that YAP and TEAD1 binding always co-occurs and is mediated by single as well as double TEAD1 motifs with a particular 3bp spacer (CATTCCNNNCATTCC). This suggests that YAP activity appears exclusively mediated by TEAD1. Despite being characterized as a promoter-binding factor YAP/TEAD actually binds predominantly to enhancers. Moreover we show that YAP is necessary for activity of the linked gene and proper chromatin state of regulated enhancers. These results establish mode of binding and activation of YAP mediated nuclear response of the Hippo pathway by TEAD1 and provide a comprehensive list and a novel class of direct target genes that are regulated distally and could be exploited for cancer therapeutics. Sequencing of ChIP and input samples for YAP1 and TEAD1 transcription factors and H3K27ac histone modification in SF268 glioblastoma cells and for YAP1 transcription factor in NCI-H2052 mesothelioma cells.
2015-08-25 | E-GEOD-61852 | biostudies-arrayexpress
Project description:BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. A critical barrier to developing an effective regimen for ICC is its intra- and inter-tumoral molecular heterogeneity, which may in part be due to its diverse cellular origin. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. These models and in silico studies led to identification of DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by both loss- and gain-of-function studies. RESULTS: Co-expression of AKT along with NICD/YAP1 in HC yielded ICC which resembled proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD induced SOX9 and YAP1 in HC-driven ICC and deletion of either significantly delays ICC development. Yap1 deletion or TEAD inhibition, but not Sox9 deletion, impaired HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
2023-07-25 | GSE200468 | GEO
Project description:BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. A critical barrier to developing an effective regimen for ICC is its intra- and inter-tumoral molecular heterogeneity, which may in part be due to its diverse cellular origin. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. These models and in silico studies led to identification of DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by both loss- and gain-of-function studies. RESULTS: Co-expression of AKT along with NICD/YAP1 in HC yielded ICC which resembled proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD induced SOX9 and YAP1 in HC-driven ICC and deletion of either significantly delays ICC development. Yap1 deletion or TEAD inhibition, but not Sox9 deletion, impaired HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
2023-07-25 | GSE200471 | GEO
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.
2015-08-25 | GSE61852 | GEO
Project description:We investigate the dependence of human malignant mesothelioma on functional TEAD transcription factors to maintain fully established tumors in vivo. We show that TEAD inhibitor K-975 stops tumor growth in vivo, eventually causing tumor regression, by downregulating TEAD activity and altering, thus, TEAD-dependent transcription in a dysfunctional Hippo genetic background. Our data validate the concept of inhibiting an activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.
2022-02-17 | GSE196726 | GEO
Project description:Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily (BID) oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. Additionally, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A demonstrating potent and specific inhibition of YAP1/TAZ-TEAD mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.
2024-03-26 | GSE249903 | GEO
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
2014-08-12 | E-GEOD-55186 | biostudies-arrayexpress
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, expression of a doxycycline-dependent dominant negative TEAD2 temporarily modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Recovery of tumor growth is associated with TEAD-dependent transcription comparable to untreated tumors, therefore, re-activation of TEAD transcription complexes.
2022-02-17 | GSE196714 | GEO