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Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines...
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Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 44557

Special Issue Editors

Prof. Wanjin Hong

E-Mail Website
Guest Editor
Institute of Molecular and Cell Biology (IMCB), A*STAR Research Entities, Singapore, Singapore
Interests: Hippo pathway; cancer signaling; cancer therapy; tumor microenvironment; YAP; TAZ; TEAD
Prof. Dr. Lanfen Chen

E-Mail Website
Guest Editor
School of Life Sciences, Xiamen University, Xiamen 361102, China
Interests: hippo signaling; Mst1/2; inflammation; immune regulation

Special Issue Information

Dear Colleagues,

The Hippo signaling pathway has emerged as an essential regulator of organ growth and tissue homeostasis. Identification of new components and definition of their underlying regulatory mechanism in Hippo signaling have been studied extensively recently. In general, the Hippo core components in mammalians consisting of serine/threonine kinase (such as MST1/2 and LATS1/2) with their scaffolding proteins (such as WW45 and MOB1, respectively) function to restrict nuclear accumulation of the co-transcriptional co-activators YAP/TAZ and their interaction with TEAD transcriptional factors. The YAP/TAZ–TEAD complex mediated transcriptional program governs the expression of many genes (up to thousands) to control cell proliferation and differentiation. Increased activities of YAP/TAZ and TEADs have been associated with diverse human cancers, and it is becoming clear that targeting Hippo signaling components, especially YAP/TAZ–TEAD complexes, is an attractive therapeutic strategy for cancer, tissue repair, and regeneration. Interestingly, some recent studies suggest that, instead of acting as a tumor suppressor pathway to restrict the activities of YAP/TAZ–TEAD, Hippo signaling could also be oncogenic in other contexts, adding more complexity and challenges to the targeting of the Hippo pathway for drug development.

This Special Issue will address the diverse mechanisms regulating Hippo signaling in various cells under different circumstances, the effects of Hippo signaling on immune cell crosstalk with tumor cells in the tumor environment or residential cells during tissue regeneration, and the different strategies to target Hippo signaling in cancer treatment, tissue repair, and regeneration.

Prof. Wanjin Hong
Prof. Lanfen Chen
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hippo signaling
  • YAP/TAZ
  • tumor
  • tissue repair, tissue regeneration, anticancer drugs
  • regenerative medicine

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Published Papers (7 papers)

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Research

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32 pages, 13392 KiB  
Article
Deletion of Cd44 Inhibits Metastasis Formation of Liver Cancer in Nf2-Mutant Mice
by Monserrat Gerardo-Ramírez, Vanessa Giam, Diana Becker, Marco Groth, Nils Hartmann, Helen Morrison, Helen L. May-Simera, Markus P. Radsak, Jens U. Marquardt, Peter R. Galle, Peter Herrlich, Beate K. Straub and Monika Hartmann
Cells 2023, 12(9), 1257; https://doi.org/10.3390/cells12091257 - 26 Apr 2023
Cited by 4 | Viewed by 2637
Abstract
Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the [...] Read more.
Primary liver cancer is the third leading cause of cancer-related death worldwide. An increasing body of evidence suggests that the Hippo tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and pathological processes in the liver. Merlin (Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of Merlin to the plasma membrane seems to be crucial for its major tumor-suppressive functions; this is facilitated by interactions with membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of Merlin have been reported in many human cancers. This study evaluated the relative contribution of CD44- and Merlin-dependent processes to the development and progression of liver tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44-knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in Nf2-mutant mice. CD44 upregulates expression of integrin β2 and promotes transendothelial migration of liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of liver cancer. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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Review

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17 pages, 1602 KiB  
Review
Transcriptional Regulation of the Hippo Pathway: Current Understanding and Insights from Single-Cell Technologies
by Sayantanee Paul, Shiqi Xie, Xiaosai Yao and Anwesha Dey
Cells 2022, 11(14), 2225; https://doi.org/10.3390/cells11142225 - 17 Jul 2022
Cited by 10 | Viewed by 5703
Abstract
The Hippo pathway regulates tissue homeostasis in normal development and drives oncogenic processes. In this review, we extensively discuss how YAP/TAZ/TEAD cooperate with other master transcription factors and epigenetic cofactors to orchestrate a broad spectrum of transcriptional responses. Even though these responses are [...] Read more.
The Hippo pathway regulates tissue homeostasis in normal development and drives oncogenic processes. In this review, we extensively discuss how YAP/TAZ/TEAD cooperate with other master transcription factors and epigenetic cofactors to orchestrate a broad spectrum of transcriptional responses. Even though these responses are often context- and lineage-specific, we do not have a good understanding of how such precise and specific transcriptional control is achieved—whether they are driven by differences in TEAD paralogs, or recruitment of cofactors to tissue-specific enhancers. We believe that emerging single-cell technologies would enable a granular understanding of how the Hippo pathway influences cell fate and drives oncogenic processes, ultimately allowing us to design better pharmacological agents against TEADs and identify robust pharmacodynamics markers of Hippo pathway inhibition. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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22 pages, 3316 KiB  
Review
New Insights into Hippo/YAP Signaling in Fibrotic Diseases
by Masum M. Mia and Manvendra K. Singh
Cells 2022, 11(13), 2065; https://doi.org/10.3390/cells11132065 - 29 Jun 2022
Cited by 46 | Viewed by 8334
Abstract
Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by [...] Read more.
Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by pathological myofibroblasts and myofibroblast-like cells. The Hippo signaling pathway is an evolutionarily conserved kinase cascade, which has been described well for its crucial role in cell proliferation, apoptosis, cell fate decisions, and stem cell self-renewal during development, homeostasis, and tissue regeneration. Recent investigations in clinical and pre-clinical models has shown that the Hippo signaling pathway is linked to the pathophysiology of fibrotic diseases in many organs including the lung, heart, liver, kidney, and skin. In this review, we have summarized recent evidences related to the contribution of the Hippo signaling pathway in the development of organ fibrosis. A better understanding of this pathway will guide us to dissect the pathophysiology of fibrotic disorders and develop effective tissue repair therapies. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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21 pages, 1811 KiB  
Review
Genomic Hippo Pathway Alterations and Persistent YAP/TAZ Activation: New Hallmarks in Head and Neck Cancer
by Farhoud Faraji, Sydney I. Ramirez, Paola Y. Anguiano Quiroz, Amaya N. Mendez-Molina and J. Silvio Gutkind
Cells 2022, 11(8), 1370; https://doi.org/10.3390/cells11081370 - 18 Apr 2022
Cited by 23 | Viewed by 5642
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune checkpoint inhibitors. The Hippo signaling pathway, originally discovered as a mechanism regulating tissue growth and organ size, transduces intracellular and extracellular signals to regulate the transcriptional co-activators YAP and TAZ. Alterations in the Hippo pathway resulting in persistent YAP and TAZ activation have emerged as major oncogenic drivers. Our analysis of the human HNSCC oncogenome revealed multiple genomic alterations impairing Hippo signaling and activating YAP and TAZ, which in turn contribute to HNSCC development. This includes mutations and deletions of the FAT1 gene (29%) and amplification of the WWTR1 (encoding TAZ, 14%) and YAP1 genes (8%), together representing one of the most genetically altered signaling mechanisms in this malignancy. Here, we discuss key elements of the mammalian Hippo pathway, detail mechanisms by which perturbations in Hippo signaling promote HNSCC initiation and progression and outline emerging strategies to target Hippo signaling vulnerabilities as part of novel multimodal precision therapies for HNSCC. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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25 pages, 3513 KiB  
Review
Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy
by Yvonne Xinyi Lim, Hexian Lin, Sock Hong Seah and Yoon Pin Lim
Cells 2021, 10(11), 3130; https://doi.org/10.3390/cells10113130 - 11 Nov 2021
Cited by 3 | Viewed by 3973
Abstract
Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation [...] Read more.
Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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13 pages, 1077 KiB  
Review
The Multiple Interactions of RUNX with the Hippo–YAP Pathway
by Linda Shyue Huey Chuang and Yoshiaki Ito
Cells 2021, 10(11), 2925; https://doi.org/10.3390/cells10112925 - 28 Oct 2021
Cited by 23 | Viewed by 4345
Abstract
The Hippo–YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog [...] Read more.
The Hippo–YAP signaling pathway serves roles in cell proliferation, stem cell renewal/maintenance, differentiation and apoptosis. Many of its functions are central to early development, adult tissue repair/regeneration and not surprisingly, tumorigenesis and metastasis. The Hippo pathway represses the activity of YAP and paralog TAZ by modulating cell proliferation and promoting differentiation to maintain tissue homeostasis and proper organ size. Similarly, master regulators of development RUNX transcription factors have been shown to play critical roles in proliferation, differentiation, apoptosis and cell fate determination. In this review, we discuss the multiple interactions of RUNX with the Hippo–YAP pathway, their shared collaborators in Wnt, TGFβ, MYC and RB pathways, and their overlapping functions in development and tumorigenesis. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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29 pages, 1444 KiB  
Review
Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine
by Evan R. Barry, Vladimir Simov, Iris Valtingojer and Olivier Venier
Cells 2021, 10(10), 2715; https://doi.org/10.3390/cells10102715 - 11 Oct 2021
Cited by 45 | Viewed by 12085
Abstract
The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for [...] Read more.
The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer. Full article
(This article belongs to the Special Issue Hippo Pathway in Cancer: Toward Anticancer Drugs or Regenerative Medicines for Tissue Repair)
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