YAP1 fusion proteins drive forebrain ependymoma tumorigenesis via the interaction with TEAD transcription factors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE110625 | GEO | 2019/08/06
REPOSITORIES: GEO
Similar Datasets
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.
2020-05-26 | PXD018131 | Pride
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.
2020-04-16 | GSE147961 | GEO
Project description:HIPPO-YAP/TAZ signaling has been implicated in supratentorial ependymoma formation from neural progenitor cells (NPC) in the brain, however, the underlying mechanisms to trigger the neural progenitor cell transformation remains elusive. Here, we uncover that patient-derived tumorigenic YAP-fusion proteins (YAP-MAMLD1 and C11ORF95-YAP) promote ependymoma tumorigenesis through forming liquid-liquid phase-separated condensates. Intrinsically disordered regions (IDR) in the fusion proteins promote oligomerization of YAP-transcriptional co-activators and self-assembly of nuclear puncta-like membrane-less organelles. Phase separation of YAP-fusion proteins further facilitates the compartmentalization of transcriptional coactivators, BRD4 and MED1, resulting in pervasive enhancer landscape changes and exclusion of transcriptional repressors such as PRC2 complexes. YAP-fusion proteins-induced nuclear puncta recruit RNA polymerase II to promote transcriptional bursting of multiple oncogenic pathways. Moreover, we show that IDR-mediated phase separation is necessary for YAP-fusion protein-induced tumor formation. Distinct YAP fusion-proteins identified in other human tumors also encompass IDR features. Together, our data suggest that IDR-mediated phase separation is an integral component of YAP-fusion protein-induced tumorigenesis and might serve as a therapeutic target in supratentorial ependymoma.
2022-10-27 | GSE181867 | GEO
Project description:HIPPO-YAP/TAZ signaling has been implicated in supratentorial ependymoma formation from neural progenitor cells (NPC) in the brain, however, the underlying mechanisms to trigger the neural progenitor cell transformation remains elusive. Here, we uncover that patient-derived tumorigenic YAP-fusion proteins (YAP-MAMLD1 and C11ORF95-YAP) promote ependymoma tumorigenesis through forming liquid-liquid phase-separated condensates. Intrinsically disordered regions (IDR) in the fusion proteins promote oligomerization of YAP-transcriptional co-activators and self-assembly of nuclear puncta-like membrane-less organelles. Phase separation of YAP-fusion proteins further facilitates the compartmentalization of transcriptional coactivators, BRD4 and MED1, resulting in pervasive enhancer landscape changes and exclusion of transcriptional repressors such as PRC2 complexes. YAP-fusion proteins-induced nuclear puncta recruit RNA polymerase II to promote transcriptional bursting of multiple oncogenic pathways. Moreover, we show that IDR-mediated phase separation is necessary for YAP-fusion protein-induced tumor formation. Distinct YAP fusion-proteins identified in other human tumors also encompass IDR features. Together, our data suggest that IDR-mediated phase separation is an integral component of YAP-fusion protein-induced tumorigenesis and might serve as a therapeutic target in supratentorial ependymoma.
2022-10-27 | GSE206926 | GEO
Project description:Giant cell ependymoma (GCE), a rare ependymoma subtype, was only recently recognised as a separate diagnostic entity with variations both in malignant potential and in course of disease. The pathogenetic mechanisms behind ependymomas remain unknown. Only one karyotyped GCE has so far been reported. We present the first genomic characterisation of a supratentorial GCE using G-band karyotyping, DNA ploidy analysis and array comparative genomic hybridisation (aCGH). The G-banded karyotype was hypodiploid with multiple monosomies, a feature present also in the previously published case and, hence, probably characteristic of these tumours. We could also analyse cytogenetically a subsequent recurrent tumour, phenotypically an anaplastic ependymoma, but exhibiting a pattern of monosomies largely similar to that found in the primary tumour, allowing a first insight into the genetic events involved also in disease progression. 2 tumour samples analysed with the control DNA (supplied by Agilent)
2010-08-30 | E-GEOD-23065 | biostudies-arrayexpress
Project description:We report an infantile case of midline ‘supratentorial ependymoma ZFTA fusion-positive’ involving both the infra- and the supra-tentorial compartments (i.e., cerebellar vermis, pons and midbrain). The radiological features, i.e., the upward displacement and compression of the supratentorial anatomical structures and the infiltrative margins of the tumour towards the cerebellar vermis, suggested an infratentorial origin of the lesion with secondary involvement of the supratentorial compartment. This case adds to the limited literature of non-hemispheric ‘supratentorial ependymoma ZFTA fusion-positive’ occurring in midline structures, both supratentorial (pineal region, thalamus) and infratentorial (cervico-medullary region and spinal cord), and in the cerebellum. These cases highlight the need to consider this entity in the differential diagnosis of paediatric non-hemispheric lesions and raise the question of whether the inclusion of the location within the WHO definition of this tumour type may be too restrictive
2023-01-01 | GSE220932 | GEO
Project description:YAP1 fusion proteins drive forebrain ependymoma tumorigenesis via the interaction with TEAD transcription factors
| PRJNA434123 | ENA
Project description:Ependymomas exist within distinct genetic subgroups, but the molecular diversity within individual ependymomas is unknown. We performed multiplatform molecular profiling of 6 spatially-distinct samples from an ependymoma with C11orf95-RELA fusion. DNA methylation and RNA sequencing distinguished clusters of samples according to neuronal development gene expression programs that could also be delineated by differences in magnetic resonance blood perfusion. Exome sequencing and phylogenetic analysis revealed epigenomic intratumor heterogeneity, and suggested that chromosomal structural alterations may precede accumulation of single nucleotide variants during ependymoma tumorigenesis. In sum, these findings shed new light on the oncogenesis and intratumor heterogeneity of ependymoma.
2019-12-20 | GSE142320 | GEO
Project description:Giant cell ependymoma (GCE), a rare ependymoma subtype, was only recently recognised as a separate diagnostic entity with variations both in malignant potential and in course of disease. The pathogenetic mechanisms behind ependymomas remain unknown. Only one karyotyped GCE has so far been reported. We present the first genomic characterisation of a supratentorial GCE using G-band karyotyping, DNA ploidy analysis and array comparative genomic hybridisation (aCGH). The G-banded karyotype was hypodiploid with multiple monosomies, a feature present also in the previously published case and, hence, probably characteristic of these tumours. We could also analyse cytogenetically a subsequent recurrent tumour, phenotypically an anaplastic ependymoma, but exhibiting a pattern of monosomies largely similar to that found in the primary tumour, allowing a first insight into the genetic events involved also in disease progression.
2010-08-30 | GSE23065 | GEO
Project description:Background: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Methods: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from eight diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were retrospectively correlated with progression-free survival (PFS). Results: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6% and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (p=0.009) and postoperative radiotherapy (p=0.007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of prognosis within molecularly defined ependymoma classes. Conclusions: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. Gross total resection and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.
2023-02-21 | GSE224218 | GEO