Glucocorticoid receptor signalling activates YAP in breast cancer

Sorrentino, Giovanni; Ruggeri, Naomi; Zannini, Alessandro; Ingallina, Eleonora; Bertolio, Rebecca; Marotta, Carolina; Neri, Carmelo; Cappuzzello, Elisa; Forcato, Mattia; Rosato, Antonio; Mano, Miguel; Bicciato, Silvio; Sal, Giannino Del

doi:10.1038/ncomms14073

Cited by 144 publications

(143 citation statements)

References 73 publications

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“…We then sought to identify the other components of the FAK-YAP cascade that may play a role in modulating the stiffness response in our system. Since remodelling of the actin cytoskeleton has been identified as a key event upstream of YAP activation [27][28][29] , we assessed its putative involvement in physiological stiffness-induced organoid growth by inhibiting acto-myosin contractility with blebbistatin 30 . Surprisingly, blebbistatin treatment significantly enhanced organoid formation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechano-modulatory synthetic niches for liver organoid derivation

Sorrentino

Rezakhani

Yildiz

et al. 2019

Preprint

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The recent demonstration that primary cells from the liver can be expanded in vitro as organoids holds enormous promise for regenerative medicine and disease modeling 1-5 . The use of threedimensional (3D) cultures based on ill-defined and potentially immunogenic matrices, however, hampers the translation of liver organoid technology into real-life applications 6 . We here used chemically defined hydrogels for the efficient derivation of both mouse and human hepatic organoids.Organoid growth was found to be highly stiffness-sensitive and dependent on yes-associated protein 1 (YAP) activity. However, in contrast to intestinal organoids 7 , YAP-mediated stiffness sensitivity was independent of acto-myosin contractility, requiring instead activation of the Src family of kinases (SFKs). Aberrant matrix stiffness on the other hand led to a shift in the progenitor phenotype, resulting in compromised proliferative capacity. Finally, we demonstrate the unprecedented establishment of biopsy-derived human liver organoids without the use of animal components at any step of the process. Our approach thus opens up exciting perspectives for the establishment of protocols for liver organoid-based regenerative medicine.

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Section: Resultsmentioning

confidence: 99%

Mechano-modulatory synthetic niches for liver organoid derivation

Sorrentino

Rezakhani

Yildiz

et al. 2019

Preprint

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“…External signals from the tumoral niche, such as hormones and cytokines, have been found to drastically regulate bCSC behavior (Batlle & Clevers, 2017). Among them, glucocorticoids have been identified as activators of the hippo/YAP pathway, a major regulator of the self-renewal program (Zanconato et al, 2016;Sorrentino et al, 2017). These observations may suggest that mifepristone could mediate its effect on the bCSC population through YAP inhibition.…”

Section: Discussionmentioning

confidence: 99%

A genome‐wide RNA i screen reveals essential therapeutic targets of breast cancer stem cells

et al. 2019

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Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome‐wide RNA interference screen to identify genes that regulate breast CSCs‐fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC‐related processes. This network analysis uncovered potential therapeutic targets controlling bCSC‐fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti‐bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor‐initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC‐related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.

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“…Hippo pathway also cross talks and integrates with many other signaling pathways to regulate growth and cell fate decisions including cellular proliferation and apoptosis. Of many, pathways like Shh (Fernandez et al, ), glucocorticoid signaling (Sorrentino et al, ), G‐protein‐coupled receptor (GPCR) (Luo & Yu, ; Miller et al, ), Notch (Totaro, Castellan, Di Biagio, & Piccolo, ), TGFβ (Grannas et al, ), TNF‐α (Dong et al, ), and EGFR‐PI3K (Xia et al, ) are well elucidated for their proper cross talk with the Hippo pathway. The upstream regulators of this pathway and their target molecules in the Hippo signaling pathway have been summarized in Table .…”

Section: Overview Of the Hippo Signaling Networkmentioning

confidence: 99%

“…Fernandez et al, 2009), glucocorticoid signaling(Sorrentino et al, 2017), G-protein-coupled receptor (GPCR)(Luo & Yu, 2019;Miller et al, 2012), Notch(Totaro, Castellan, Di Biagio, & Piccolo, 2018), TGFβ(Grannas et al, 2015), TNF-α(Dong et al, 2015), and EGFR-PI3K are well elucidated for their proper cross talk with the Hippo pathway. The upstream regulators of this pathway and their target molecules in the Hippo signaling pathway have been summarized in Table 2.…”

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confidence: 99%

The emerging role of Hippo signaling in neurodegeneration

Sahu

Mondal

2019

J of Neuroscience Research

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Neurodegeneration refers to the complex process of progressive degeneration or neuronal apoptosis leading to a set of incurable and debilitating conditions. Physiologically, apoptosis is important in proper growth and development. However, aberrant and unrestricted apoptosis can lead to a variety of degenerative conditions including neurodegenerative diseases. Although dysregulated apoptosis has been implicated in various neurodegenerative disorders, the triggers and molecular mechanisms underlying such untimely and faulty apoptosis are still unknown. Hippo signaling pathway is one such apoptosis‐regulating mechanism that has remained evolutionarily conserved from Drosophila to mammals. This pathway has gained a lot of attention for its tumor‐suppressing task, but recent studies have emphasized the soaring role of this pathway in inflaming neurodegeneration. In addition, strategies promoting inactivation of this pathway have aided in the rescue of neurons from anomalous apoptosis. So, a thorough understanding of the relationship between the Hippo pathway and neurodegeneration may serve as a guide for the development of therapy for various degenerative diseases. The current review focuses on the mechanism of the Hippo signaling pathway, its upstream and downstream regulatory molecules, and its role in the genesis of numerous neurodegenerative diseases. The recent efforts employing the Hippo pathway components as targets for checking neurodegeneration have also been highlighted.

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Glucocorticoid receptor signalling activates YAP in breast cancer

Cited by 144 publications

References 73 publications

Mechano-modulatory synthetic niches for liver organoid derivation

Mechano-modulatory synthetic niches for liver organoid derivation

A genome‐wide RNA i screen reveals essential therapeutic targets of breast cancer stem cells

The emerging role of Hippo signaling in neurodegeneration

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