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The Hippo pathway: an emerging role in urologic cancers.

01 Jan 2021-Vol. 9, Iss: 4, pp 301-317
TL;DR: The Hippo pathway core kinases MST1/2 and LATS 1/2 in mammals phosphorylate and inactivate YAP1 signaling to prevent cancer growth.
Abstract: The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer.
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TL;DR: This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.
Abstract: Acute kidney injury (AKI) is a significant clinical complication with a substantial impact on morbidity and mortality, for which therapeutic options remain limited. The Hippo signaling pathway is an evolutionarily conserved pathway implicated in cell proliferation, dedifferentiation, and apoptosis via phosphorylation and inactivation of its downstream effectors Yes-associated protein (YAP)/ transcriptional co-activator with PDZ-binding motif (TAZ). Recent studies have revealed that the Hippo pathway plays a pivotal role in the pathogenesis and repair of AKI. The Hippo pathway can mediate renal dysfunction through modulation of mitochondrial apoptosis under AKI conditions. Transient activation of YAP/TAZ in the acute phase of AKI may benefit renal recovery and regeneration, whereas persistent activation of YAP/TAZ in severe AKI may lead to maladaptive repair and transition to chronic kidney disease. This review aims to summarize recent findings on the associations between the Hippo pathway and AKI and to identify new therapeutic targets and strategies for AKI.

2 citations

Journal ArticleDOI
TL;DR: In this paper , an early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening, and the results showed that the early intervention showed promising results.
Abstract: Background Early detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined. Methods STs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the “early” cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced “later” canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening. Results Biopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention. Conclusions The study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

1 citations

Journal ArticleDOI
TL;DR: In this paper , the authors investigated the mechanism by which MST1 regulates EPHA3 and revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA-3 transcription.
Abstract: The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell-cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell-cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated by YAP1/TEAD1 of the Hippo pathway, suggesting that it is sensitive to cell contact-dependent interactions.
Journal ArticleDOI
01 Dec 2022-Heliyon
TL;DR: In this paper , the role of interferon-γ related genes (IRGs) in the prognosis and immunotherapy of bladder cancer (BC) was explored through Cox regression analyses.
References
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Journal ArticleDOI
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).

24,414 citations

Journal ArticleDOI
TL;DR: A practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics, which makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries.
Abstract: The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.

10,947 citations

Journal ArticleDOI
09 Jun 2011-Nature
TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.
Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

4,120 citations

Journal ArticleDOI
TL;DR: Treatment with atezolizumab resulted in a significantly improved RECIST v1.1 response rate, compared with a historical control overall response rate of 10%, and Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolediazepine.

2,934 citations

Journal ArticleDOI
Dan R. Robinson1, Eliezer M. Van Allen2, Eliezer M. Van Allen3, Yi-Mi Wu1, Nikolaus Schultz4, Robert J. Lonigro1, Juan Miguel Mosquera, Bruce Montgomery5, Mary-Ellen Taplin2, Colin C. Pritchard5, Gerhardt Attard6, Gerhardt Attard7, Himisha Beltran, Wassim Abida4, Robert K. Bradley5, Jake Vinson4, Xuhong Cao1, Pankaj Vats1, Lakshmi P. Kunju1, Maha Hussain1, Felix Y. Feng1, Scott A. Tomlins, Kathleen A. Cooney1, David Smith1, Christine Brennan1, Javed Siddiqui1, Rohit Mehra1, Yu Chen4, Yu Chen8, Dana E. Rathkopf4, Dana E. Rathkopf8, Michael J. Morris4, Michael J. Morris8, Stephen B. Solomon4, Jeremy C. Durack4, Victor E. Reuter4, Anuradha Gopalan4, Jianjiong Gao4, Massimo Loda, Rosina T. Lis2, Michaela Bowden9, Michaela Bowden2, Stephen P. Balk10, Glenn C. Gaviola9, Carrie Sougnez3, Manaswi Gupta3, Evan Y. Yu5, Elahe A. Mostaghel5, Heather H. Cheng5, Hyojeong Mulcahy5, Lawrence D. True11, Stephen R. Plymate5, Heidi Dvinge5, Roberta Ferraldeschi7, Roberta Ferraldeschi6, Penny Flohr7, Penny Flohr6, Susana Miranda6, Susana Miranda7, Zafeiris Zafeiriou6, Zafeiris Zafeiriou7, Nina Tunariu7, Nina Tunariu6, Joaquin Mateo6, Joaquin Mateo7, Raquel Perez-Lopez6, Raquel Perez-Lopez7, Francesca Demichelis8, Francesca Demichelis12, Brian D. Robinson, Marc H. Schiffman8, David M. Nanus, Scott T. Tagawa, Alexandros Sigaras8, Kenneth Eng8, Olivier Elemento8, Andrea Sboner8, Elisabeth I. Heath13, Howard I. Scher8, Howard I. Scher4, Kenneth J. Pienta14, Philip W. Kantoff2, Johann S. de Bono7, Johann S. de Bono6, Mark A. Rubin, Peter S. Nelson, Levi A. Garraway2, Levi A. Garraway3, Charles L. Sawyers4, Arul M. Chinnaiyan 
21 May 2015-Cell
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.

2,713 citations