The Hippo tranducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation
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ABSTRACT:
PROVIDER: PRJNA238828 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1172110.fastq.gz | Fastqsanger.gz | |||
| SRR1172111.fastq.gz | Fastqsanger.gz | |||
| SRR1172112.fastq.gz | Fastqsanger.gz | |||
| SRR1172113.fastq.gz | Fastqsanger.gz |
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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: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.
2014-08-12 | GSE55186 | GEO
Project description:Doxycycline-inducible YAP1 S127A-driven rhabdomyosarcoma (RMS) tumors, control skeletal muscle and regressed tumors following YAP1 normalization by doxycycline withdrawal were compared to determine the YAP1-regulated gene expression profile relevant to RMS formation. To characterize the role of YAP1 in embryonal RMS at the molecular level and identify a gene signature for YAP1 activity readout, we compared the gene expression profiles of our YAP1-driven ERMS with control donor skeletal muscle (SKM) and doxycycline-withdrawn regressing tumors by microarray (doxycycline withdrawal for 3 or 6 days; OFF3 and OFF6, respectively). We next extracted a list of genes regulated by YAP1 in our YAP1-driven ERMS tumors (TUM) versus the 3 other conditions: skeletal muscle control (SKM), Doxycycline-withdrawn 3 days (OFF3) and 6 days (OFF6). The overlap between the 3 lists identified a subset of 633 common upregulated genes, named the YAP1-ERMS_UP signature, as well as 249 common downregulated genes, termed the YAP1-ERMS_DOWN signature. Proliferative pathways and transcriptional targets of E2F factors were highlighted in the YAP1-ERMS_UP genes, while muscle differentiation and trancriptional targets of myogenic factors Myod1 and Mef2 were highlighted in the YAP1-ERMS_DOWN genes. Tumor regression conditions (OFF3 days; OFF6 days) as well as control muscle (CTL) were compared with tumors at day 0 of doxycycline withdrawal (TUM). 3 samples for each conditions were used.
2014-08-12 | E-GEOD-47198 | biostudies-arrayexpress
Project description:Doxycycline-inducible YAP1 S127A-driven rhabdomyosarcoma (RMS) tumors, control skeletal muscle and regressed tumors following YAP1 normalization by doxycycline withdrawal were compared to determine the YAP1-regulated gene expression profile relevant to RMS formation. To characterize the role of YAP1 in embryonal RMS at the molecular level and identify a gene signature for YAP1 activity readout, we compared the gene expression profiles of our YAP1-driven ERMS with control donor skeletal muscle (SKM) and doxycycline-withdrawn regressing tumors by microarray (doxycycline withdrawal for 3 or 6 days; OFF3 and OFF6, respectively). We next extracted a list of genes regulated by YAP1 in our YAP1-driven ERMS tumors (TUM) versus the 3 other conditions: skeletal muscle control (SKM), Doxycycline-withdrawn 3 days (OFF3) and 6 days (OFF6). The overlap between the 3 lists identified a subset of 633 common upregulated genes, named the YAP1-ERMS_UP signature, as well as 249 common downregulated genes, termed the YAP1-ERMS_DOWN signature. Proliferative pathways and transcriptional targets of E2F factors were highlighted in the YAP1-ERMS_UP genes, while muscle differentiation and trancriptional targets of myogenic factors Myod1 and Mef2 were highlighted in the YAP1-ERMS_DOWN genes.
2014-08-12 | GSE47198 | GEO
Project description:BMI1 regulates myogenic differentiation, Hippo signaling, and oncogene expression in embryonal rhabdomyosarcoma.
| PRJEB12396 | ENA
Project description:The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC-Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
| S-EPMC4995731 | biostudies-literature
Project description:Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However, YAP1 is rarely mutated in human ERMS. Instead, the most common mutations in ERMS are oncogenic RAS mutations. First, to compare YAP1 S127A and KRAS G12V-driven rhabdomyosarcomas, we re-analysed gene expression microarray datasets from mouse rhabdomyosarcomas caused by these genes. This revealed that only 20% of the up or downregulated genes are identical, suggesting substantial differences in gene expression between YAP and KRAS-driven rhabdomyosarcomas. As oncogenic RAS has been linked to YAP in other types of cancer, we also tested whether KRAS G12V alone or in combination with loss of p53 and p16 activates YAP in myoblasts. We found that neither KRAS G12V alone nor KRAS G12V combined with loss of p53 and p16 activated Yap or Yap/Taz-Tead1-4 transcriptional activity in C2C12 myoblasts or U57810 cells. In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of KRAS G12V expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between KRAS G12V and YAP1 S127A-driven tumours.
| S-EPMC6199242 | biostudies-literature
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. To identify the role of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line, we performed microarray after knocking down YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (3 siLuc, 3 siYAP1, 3 siTEAD1, 3 siKLF5)
2013-12-31 | E-GEOD-32597 | 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, 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.
2014-12-31 | GSE54617 | GEO