Cancers

Editorial

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4 pages, 200 KiB

Open AccessEditorial

The Telluride YAP/TAZ and TEAD Workshop: A Small Meeting with a Big Impact

by Guy L. Weinberg, Peter Salamon and John M. Lamar

Cancers 2023, 15(19), 4717; https://doi.org/10.3390/cancers15194717 - 25 Sep 2023

Viewed by 1061

Abstract

Funding the research needed to advance our understanding of rare cancers is very challenging [...] Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

Research

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25 pages, 11226 KiB

Open AccessArticle

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

by Ryan Kanai, Emily Norton, Patrick Stern, Richard O. Hynes and John M. Lamar

Cancers 2024, 16(5), 852; https://doi.org/10.3390/cancers16050852 - 20 Feb 2024

Viewed by 889

Abstract

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in [...] Read more.

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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15 pages, 4682 KiB

Open AccessArticle

Genome-Wide Characterization of TAZ Binding Sites in Mammary Epithelial Cells

by Tao Liu, Jiaojiao Zhou, Yanmin Chen, Jia Fang, Song Liu, Costa Frangou, Hai Wang and Jianmin Zhang

Cancers 2023, 15(19), 4713; https://doi.org/10.3390/cancers15194713 - 25 Sep 2023

Viewed by 960

Abstract

The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast [...] Read more.

The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast cancer (BLBC) patients. The oncogenic activity of TAZ involves the regulation of diverse signal transduction pathways that direct processes such as cell proliferation, migration, and resistance to apoptosis, albeit through poorly characterized gene expression programs. Here, using a tet-inducible system in mammary epithelial MCF10A cells, we have characterized the TAZ-regulated transcription program using RNA sequencing in a temporal and spatial manner. We further identified global TAZ binding sites at different TAZ activation time points by chromatin immunoprecipitation (ChIP) sequencing analysis. We found that the vast majority of TAZ was rapidly localized in enhancer regions at the early TAZ activation time point and then gradually spread to promoter regions. TAZ bound to enhancer regions following a switch in potential TEAD and FOSL2 transcription factor motifs. Furthermore, the ATAC sequencing analysis indicated that TAZ activation led to chromatin structural alterations. Together, our results have revealed the landscape of genome-wide TAZ binding sites and may lead to improvements in the current understanding of how TAZ regulates the gene expression program that contributes to the development of breast cancer. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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Review

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32 pages, 3101 KiB

Open AccessReview

New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

by Yang Zhao, Marisela Sheldon, Yutong Sun and Li Ma

Cancers 2023, 15(23), 5497; https://doi.org/10.3390/cancers15235497 - 21 Nov 2023

Cited by 4 | Viewed by 2728

Abstract

The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation [...] Read more.

The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ’s biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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27 pages, 2383 KiB

Open AccessReview

Nuclear Import and Export of YAP and TAZ

by Michael Kofler and András Kapus

Cancers 2023, 15(20), 4956; https://doi.org/10.3390/cancers15204956 - 12 Oct 2023

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Abstract

Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they [...] Read more.

Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they also play key roles in tumorigenesis and metastasis formation. Their activity is primarily regulated by their localization, that is, Hippo pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details of such prevailing retention models have been elucidated, much less is known about their actual nuclear traffic: import and export. Although their size is not far from the cutoff for passive diffusion through the nuclear pore complex (NPC), and they do not contain any classic nuclear localization (NLS) or nuclear export signal (NES), evidence has been accumulating that their shuttling involves mediated and thus regulatable/targetable processes. The aim of this review is to summarize emerging information/concepts about their nucleocytoplasmic shuttling, encompassing the relevant structural requirements (NLS, NES), nuclear transport receptors (NTRs, karyophererins), and NPC components, along with the potential transport mechanisms and their regulation. While dissecting retention vs. transport is often challenging, the emerging picture suggests that YAP/TAZ shuttles across the NPC via multiple, non-exclusive, mediated mechanisms, constituting a novel and intriguing facet of YAP/TAZ biology. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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24 pages, 4148 KiB

Open AccessReview

Multi-Functional Regulation by YAP/TAZ Signaling Networks in Tumor Progression and Metastasis

by Hannah L. Thrash and Ann Marie Pendergast

Cancers 2023, 15(19), 4701; https://doi.org/10.3390/cancers15194701 - 24 Sep 2023

Cited by 2 | Viewed by 1731

Abstract

The Hippo pathway transcriptional co-activators, YES-associated protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ), have both been linked to tumor progression and metastasis. These two proteins possess overlapping and distinct functions, and their activities lead to the expression of genes involved [...] Read more.

The Hippo pathway transcriptional co-activators, YES-associated protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ), have both been linked to tumor progression and metastasis. These two proteins possess overlapping and distinct functions, and their activities lead to the expression of genes involved in multiple cellular processes, including cell proliferation, survival, and migration. The dysregulation of YAP/TAZ-dependent cellular processes can result in altered tumor growth and metastasis. In addition to their well-documented roles in the regulation of cancer cell growth, survival, migration, and invasion, the YAP/TAZ-dependent signaling pathways have been more recently implicated in cellular processes that promote metastasis and therapy resistance in several solid tumor types. This review highlights the role of YAP/TAZ signaling networks in the regulation of tumor cell plasticity mediated by hybrid and reversible epithelial–mesenchymal transition (EMT) states, and the promotion of cancer stem cell/progenitor phenotypes. Mechanistically, YAP and TAZ regulate these cellular processes by targeting transcriptional networks. In this review, we detail recently uncovered mechanisms whereby YAP and TAZ mediate tumor growth, metastasis, and therapy resistance, and discuss new therapeutic strategies to target YAP/TAZ function in various solid tumor types. Understanding the distinct and overlapping roles of YAP and TAZ in multiple cellular processes that promote tumor progression to metastasis is expected to enable the identification of effective therapies to treat solid tumors through the hyper-activation of YAP and TAZ. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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38 pages, 3790 KiB

Open AccessReview

The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment

by Reza Bayat Mokhtari, Neda Ashayeri, Leili Baghaie, Manpreet Sambi, Kosar Satari, Narges Baluch, Dmitriy A. Bosykh, Myron R. Szewczuk and Sayan Chakraborty

Cancers 2023, 15(13), 3468; https://doi.org/10.3390/cancers15133468 - 02 Jul 2023

Cited by 7 | Viewed by 3121

Abstract

Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of [...] Read more.

Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of the TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override the growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary of the contrasting roles of YAP/TAZ during normal tissue homeostasis versus tumor initiation and progression. In addition to upstream factors that regulate YAP/TAZ in the TME, critical insights on the emerging functions of YAP/TAZ in immune suppression and abnormal vasculature development during tumorigenesis are illustrated. Lastly, we discuss the current methods that intervene with the YAP/TAZ-TEAD oncogenic signaling pathway and the emerging applications of combination therapies, gut microbiota, and epigenetic plasticity that could potentiate the efficacy of chemo/immunotherapy as improved cancer therapeutic strategies. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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13 pages, 3321 KiB

Open AccessReview

Current Model Systems for Investigating Epithelioid Haemangioendothelioma

by Emily Neil and Valerie Kouskoff

Cancers 2023, 15(11), 3005; https://doi.org/10.3390/cancers15113005 - 31 May 2023

Viewed by 1759

Abstract

Epithelioid haemangioendothelioma (EHE) is a rare sarcoma of the vascular endothelium with an unpredictable disease course. EHE tumours can remain indolent for long period of time but may suddenly evolve into an aggressive disease with widespread metastases and a poor prognosis. Two mutually [...] Read more.

Epithelioid haemangioendothelioma (EHE) is a rare sarcoma of the vascular endothelium with an unpredictable disease course. EHE tumours can remain indolent for long period of time but may suddenly evolve into an aggressive disease with widespread metastases and a poor prognosis. Two mutually exclusive chromosomal translocations define EHE tumours, each involving one of the transcription co-factors TAZ and YAP. The TAZ-CAMTA1 fusion protein results from a t(1;3) translocation and is present in 90% of EHE tumours. The remaining 10% of EHE cases harbour a t(X;11) translocation, resulting in the YAP1-TFE3 (YT) fusion protein. Until recently, the lack of representative EHE models made it challenging to study the mechanisms by which these fusion proteins promote tumorigenesis. Here, we describe and compare the recently developed experimental approaches that are currently available for studying this cancer. After summarising the key findings obtained with each experimental approach, we discuss the advantages and limitations of these different model systems. Our survey of the current literature shows how each experimental approach can be utilised in different ways to improve our understanding of EHE initiation and progression. Ultimately, this should lead to better treatment options for patients. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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