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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE137040 | 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.

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.

| S-EPMC7397849 | biostudies-literature

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

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 | GSE137038 | GEO

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

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)

2020-08-04 | GSE144581 | GEO

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

| PRJNA564312 | ENA

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]

| PRJNA564315 | ENA

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]

| PRJNA564316 | ENA

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

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

| PRJNA604071 | ENA

Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma.

Project description:Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescent in-situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.

| S-EPMC6715383 | biostudies-literature

AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis.

Project description:Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1-YAP1-CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1-CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.

| S-EPMC7253359 | biostudies-literature

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