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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis[RNASeq]

ABSTRACT: Several different YAP1 gene fusions have been identified in various human cancers. We performed RNA sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3, as well as on whole tumor lysates from mouse brain tumors generated by intra-cranial expression of either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137038 | GEO | 2020/08/04

REPOSITORIES: GEO

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [mouse RNA-seq]

Project description:Several different YAP1 gene fusions have been identified in various human cancers. We performed RNA sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3, as well as on whole tumor lysates from mouse brain tumors generated by intra-cranial expression of either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3.

2020-08-04 | GSE137039 | GEO

Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [Cut&Run ChIP-seq]

Project description:Several different YAP1 gene fusions have been identified in various human cancers. We performed Cut and Run Chip sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, wild type YAP1, wild type MAMLD1, wild type FAM118B, wild type TFE3, or S127/397A-YAP1 (all HA tagged at the N'terminus)

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis

Project description:Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis[RNASeq]

Project description:Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis[RNASeq]

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis.

Project description:YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [mouse RNA-seq]

Project description:Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [mouse RNA-seq]

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YAP1 fusion proteins drive forebrain ependymoma tumorigenesis via the interaction with TEAD transcription factors

Project description:A mouse model has been generated resembling human YAP1 fusion-positive supratentorial ependymoma. We show that the YAP1-MAMLD1 fusion, which is the most recurrent fusion in this distinct type of ependymomas, is able to drive malignant transformation in mice. The resulting brain tumors resemble histo-molecular characteristics of their human counterparts.

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Project description:Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [Cut&Run ChIP-seq]

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Metabolic reprogramming driven by TFE3 fusions unveils novel vulnerabilities in translocation renal cell carcinoma [RNA-Seq]

Project description:Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other RCCs. The transcriptional program driven by TFE3 fusions sustains high NRF2 signaling and glutathione production, which offsets reactive oxygen species generated by OXPHOS but renders tRCC cells sensitive to reductive stress. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to maintaining this metabolic balance, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1compromises tRCC cell growth by stabilizing HIF-1a and promoting glycolytic reprogramming. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.

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TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma

Project description:TFE3 is a member of the basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS) we interrogated a number of oncogenic mechanisms of TFE3-SF-containing fusions. We demonstrate that inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. Using HTHCS combined with FRET technology, we screened the FDA approved drugs library LOPAC and a small molecule library (Microsource) and identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D models utilizing patient derived xenolines and xenografts expressing TFE3-SF. The antihistamine terfenadine demonstrated decreased cell proliferation and reduced in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.

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