The prognosis for patients with non‑small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5‑year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5‑30 mm, or whole‑brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial‑to‑mesenchymal transition, overexpression of programmed cell death‑ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes‑associated protein‑1, on cerebral metastases originating from lung cancer.

During the last 20 years, molecular alterations have gained increasing significance in the diagnosis and biological assessment of tumors. Gliomas represent the largest group of tumors of the central nervous system, and the main aim of this review is to present the current knowledge on molecular pathways and their alterations in gliomas. A wide range of new insights has been gained, including evidence for the involvement of the WNT pathway or the hippo pathway in the pathobiology of gliomas, indicating a broad involvement of different pathways formerly not considered to play a central role in gliomas. Even new aspects of angiogenic, apoptotic, and metabolic pathways are presented, as well as the rapidly growing field of epigenetic processes, including non-coding RNAs. The two major conclusions drawn from the present review are the distinct interconnectivity of the whole spectrum of molecular pathways and the prominent role of non-coding RNAs, especially circular RNAs, in the regulation of specific targets. All these new insights are discussed, even considering the topic of the resistance to therapy of gliomas, along with aspects that are still incompletely understood, like the role of hydroxymethylation, or even ferroptosis, in the pathobiology of gliomas.

UNASSIGNED: The Hippo pathway represents a new opportunity for the treatment of cancer. Overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) or TEAD has been demonstrated in cancers and YAP mediates resistance to cancer drugs. Since 2018, the potential of this pathway has been illustrated by numerous articles and patents and the first drugs entering in clinical trial phase 1.
UNASSIGNED: This review is limited to published patent applications that have disclosed direct small-molecule inhibitors of the YAP/TAZ-TEAD interaction.
UNASSIGNED: The YAP/TAZ-TEAD transcriptional complex is a promising target for the treatment of cancer. Approximately 30 international patents (used database: Sci-finder, query: TEAD; documents: patents; period: from 2017-January 2022) that disclose TEAD transcriptional inhibitors have been filled since 2018. The mechanism of action is not always described in the patents, we can divide the drugs into three different categories: (i) external TEAD ligands; (ii) non-covalent TEAD ligands of the palmitate pocket; (iii) covalent TEAD ligands, which bind into the palmitate pocket. The first molecules in clinical trial phase 1 are non-covalent TEAD ligands. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.

Cancer is recognized as the leading cause of death worldwide. The hippo signaling pathway regulates organ size by balancing cell proliferation and cell death; hence dysregulation of the hippo pathway promotes cancer‑like conditions. miRNAs are a type of non‑coding RNA that have been shown to regulate gene expression. miRNA levels are altered in various classes of cancer. Researchers have also uncovered a crosslinking between miRNAs and the hippo pathway, which has been linked to cancer. The components of the hippo pathway regulate miRNA synthesis, and various miRNAs regulate the components of the hippo pathway both positively and negatively, which can lead to cancer‑like conditions. In the present review article, the mechanism behind the hippo signaling pathway and miRNAs biogenesis and crosslinks between miRNAs and the hippo pathway, which result in cancer, shall be discussed. Furthermore, the article will cover miRNA‑related therapeutics and provide an overview of the development of resistance to anticancer drugs. Understanding the underlying processes would improve the chances of developing effective cancer treatment therapies.

Intestinal cell stemness, proliferation and differentiation are complex processes all occurring in distinct compartments of the crypt that need to be closely regulated to ensure proper epithelial renewal. The involvement of the Hippo pathway in intestinal epithelial proliferation and regeneration after injury via the regulation of its effectors YAP1 and TAZ has been well-documented over the last decade. The implication of YAP1 and TAZ on intestinal epithelial cell differentiation is less clear. Using intestinal cell models in which the expression of YAP1 and TAZ can be modulated, our group showed that YAP1 inhibits differentiation of the two main intestinal epithelial cell types, goblet and absorptive cells through a specific mechanism involving the repression of prodifferentiation transcription factor CDX2 expression. Further analysis provided evidence that the repressive effect of YAP1 on intestinal differentiation is mediated by regulation of the Hippo pathway by Src family kinase activity. Interestingly, the TAZ paralog does not seem to be involved in this process, which provides another example of the lack of perfect complementarity of the two main Hippo effectors.

The Hippo-YAP pathway is fast becoming a key instrument in regulating cancers. Binary oppositions, also known as the Yin-Yang dynamics in Chinese, have emerged in its effects. Some oppositions are attributable to in vitro and in vivo experimental conditions, some are due to differences between cancers or species, some are derived from its inherent duality endowed by upstream and downstream signaling, and some are yet unresolved mysteries. However, as bewildering they are, few have been noticed and defined so far. In this review, we first look back on the Hippo pathway which was initially identified more than a decade ago. We then focus on tumor biology, especially some latest popular mechanisms that regulate tumor cell survival, such as ferroptosis, autophagy, and apoptosis. The third chapter is concerned with the findings of the relationship between the Hippo pathway and tumor immunity on the microenvironment in which tumor cells progress. In each of these main sections the contradictory points of the Hippo pathway are elucidated and thoroughly examined. On one hand, the Yin-Yang dynamics of the Hippo pathway brings about considerable challenges for current research; on the other hand, this work will generate fresh insight into it and offer opportunities for subsequent drug development for cancer and regenerative medicine.

BACKGROUND: The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression.
METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched.
RESULTS: The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors.
CONCLUSIONS: This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs.

UNASSIGNED: The Hippo pathway is a developmental pathway recently discovered in Drosophila melanogaster; in mammals it normally controls organ development and wound healing. Hippo signaling is deregulated in breast cancer (BC). MST1/2 and LATS1/2 kinases are the upstream molecular elements of Hippo signaling which phosphorylate and regulate the two effectors of Hippo signaling, YAP1 and TAZ cotranscriptional activators. The two molecular effectors of the Hippo pathway facilitate their activity through TEAD transcription factors. Several molecular pathways with known oncogenic functions cross-talk with the Hippo pathway.
UNASSIGNED: A systematic review studying the correlation of the Hippo pathway with BC tumorigenesis, prognosis, and treatment was performed.
UNASSIGNED: Recent literature highlights the critical role of Hippo signaling in a wide spectrum of biological mechanisms in BC.
UNASSIGNED: The Hippo pathway has a crucial position in BC molecular biology, cellular behavior, and response to treatment. Targeting the Hippo pathway could potentially improve the prognosis and outcome of BC patients.

Introduction: The Hippo pathway represents a new and intriguing opportunity for the treatment of cancer. Activation or overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) has been shown to lead to cell transformation and tumor development. To date, no small molecule compounds targeting this pathway have progressed to the clinic, illustrating both its potential and its infancy. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed direct small molecule inhibitors of the YAP/TAZ-transcriptional enhanced associate domain (TEAD) interaction. Expert opinion: The Hippo pathway, and specifically the YAP/TAZ-TEAD transcriptional complex, has been shown to be a promising target for the treatment of cancer. However, reports in the area of small molecules targeting the YAP/TAZ-TEAD transcriptional activation complex are few and far between, with only two published patent applications that disclose compounds with moderate levels of pathway inhibition. Interestingly, the YAP/TAZ-TEAD complex can be disrupted through two very different mechanisms, one of which is direct inhibition at either the Ω-loop or the α-helix of the YAP-TEAD binding interface. Both YAP protein segments have been shown to be important to TEAD binding. Alternatively, it has been reported that allosteric inhibition might be accomplished by binding the TEAD palmitoylation pocket, thus disrupting YAP binding and also native protein stabilization. The advantages and liabilities of disrupting the YAP/TAZ-TEAD complex through these two distinct mechanisms have yet to be fully elucidated, and it remains unclear which approach, if any, will generate the first clinical stage inhibitor of the Hippo pathway.