Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine

Dey, Anwesha; Varelas, Xaralabos; Guan, Kun‐Liang

doi:10.1038/s41573-020-0070-z

Cited by 535 publications

(410 citation statements)

References 198 publications

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“…Thus, whilst naïve SFs display hypermethylation of the promoter and TSS regions of genes associated with regulation of pluripotency and (oncofetal) development, many of these sites are hypomethylated and potentially derepressed in CIA-, but not ES-62-CIA-, SFs. By contrast, whilst elements associated with the FoxO, Hippo and Wnt signalling pathways that are key to the regulation of these processes (stem cell biology, cilia and intercellular communication, organ development, immunomodulation, tissue repair and regeneration and ageing 64, 84, 85 ) are similarly hypomethylated in CIA SFs and hypermethylated in ES-62-CIA, these genes are also hypomethylated in naïve SFs. Of related interest, we have previously shown ES-62 to strongly induce negative regulators (WIF1, AMOTL2 and CRYBB2) of Wnt signalling in RA synovial membranes, in vitro 86 .…”

Section: Discussionmentioning

confidence: 92%

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Corbet

Pineda

Yang

et al. 2020

Preprint

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The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an “aggressive” pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted “safe” phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct “protective” phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.

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Section: Discussionmentioning

confidence: 92%

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Corbet

Pineda

Yang

et al. 2020

Preprint

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“…Copy number amplifications of 11q22 and 3q25 (where YAP1 and WWTR1 are located, respectively) are common events reported in OSCC, often in mutual exclusive manner ( Campbell et al, 2018 ; Wang et al, 2018 ). These two genes are the major effectors negatively regulated by the Hippo pathway that is increasingly reported to play multiple roles in carcinogenesis, as reviewed comprehensively in recent years ( Dey et al, 2020 ; Santos-de-Frutos et al, 2019 ). However, the majority of the studies focused on either one of the paralogs or had assumed similar functions between paralogs ( Santos-de-Frutos et al, 2019 ; Zanconato et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Chai

Yee

Price

et al. 2020

eLife

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New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favourable response towards immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1.

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“…The Hippo pathway is closely related to the development and progression of breast cancer and has emerged as a linchpin in breast cancer therapy resistance (Gujral and Kirschner, 2017) (Shi et al, 2015). Hippo pathway effectors, such as YAP, TAZ, and TEAD, have been employed as drug targets to hit other signaling pathways (Dey et al, 2020). In ovarian cancer, YAP expression is associated with PI3K inhibitor resistance (Muranen et al, 2016).…”

Section: Alterations Of Hippo Pathwaymentioning

confidence: 99%

Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

Zou

Zhang

et al. 2020

Front. Pharmacol.

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As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

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Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine

Cited by 535 publications

References 198 publications

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway

Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

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