The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ

Chang, Lei; Azzolin, Luca; Biagio, Daniele Di; Zanconato, Francesca; Battilana, Giusy; Xiccato, Romy Lucon; Aragona, Mariaceleste; Giulitti, Stefano; Panciera, Tito; Gandin, Alessandro; Sigismondo, Gianluca; Krijgsveld, Jeroen; Fassan, Matteo; Brusatin, Giovanna; Cordenonsi, Michelangelo; Piccolo, Stefano

doi:10.1038/s41586-018-0658-1

Cited by 253 publications

(200 citation statements)

References 37 publications

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“…Once activated in tumour epithelial cells by nuclear translocation and interaction with the transcription factor TEAD, YAP/TAZ elicit a number of pro‐invasive pathways, such as the mTOR/cyclin D1‐mediated hyper‐proliferation, the AKT‐mediated escape from apoptosis, and the activation of the EMT program endowing tumoural cells with mesenchymal properties . Recent data show that alternative to association with TEAD, YAP/TAZ nuclear activity is inhibited by its association with the switching defective/sucrose non‐fermenting (SWI/SNF) chromatin‐remodelling complex through ARID1A, whose genetic inactivation has been reported in about 7% of iCCA . The association between ARID1A–SWI/SNF and YAP/TAZ is finely regulated by cellular mechanotransduction: whereas soft ECM favours YAP/TAZ inhibitory sequestration within the ARID1A‐containing SWI/SNF, conversely stiff ECM induces YAP/TAZ detachment from SWI/SNF and their binding to TEAD .…”

Section: The Evolving Role Of the Ecm In Ccamentioning

confidence: 99%

“…whereas soft ECM favours YAP/TAZ inhibitory sequestration within the ARID1A-containing SWI/SNF, conversely stiff ECM induces YAP/TAZ detachment from SWI/SNF and their binding to TEAD. 53 Notably, a stiff ECM enhances the activity of YAP/TAZ not only in cancer cells but also in stromal cells, including CAFs. Active nuclear YAP was expressed by CAFs, and YAP depletion in CAFs reduced their tumour-promoting functions.…”

Section: The E Volving Role Of the Ecm In CC Amentioning

confidence: 99%

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The tumour microenvironment and immune milieu of cholangiocarcinoma

Fabris

Perugorria

Mertens

et al. 2019

Liver International

139

124

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Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer‐associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour‐associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour‐promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

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Section: The Evolving Role Of the Ecm In Ccamentioning

confidence: 99%

Section: The E Volving Role Of the Ecm In CC Amentioning

confidence: 99%

The tumour microenvironment and immune milieu of cholangiocarcinoma

Fabris

Perugorria

Mertens

et al. 2019

Liver International

139

124

View full text Add to dashboard Cite

show abstract

“…107,108 A recent study has proposed a role for ARID1A in negative regulation of YAP/TAZ activity in the nucleus, linking this regulatory mechanism to mechanosignalling. 109 In that model, liver-specific Arid1a ablation was per se inconsequential, but led to the development of iCCA in the context of liver damage and was associated with tissue stiffening. 109 Loss of PBRM1 was reported to occur late in iCCA.…”

Section: Epigenetic And/or Ddr Pathways Linked To Bap1 Pbrm1 and Amentioning

confidence: 99%

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Fouassier

Marzioni

Afonso

et al. 2019

Liver International

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Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour cell‐intrinsic alterations at the genetic and epigenetic level but also pro‐tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumour stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale‐based and genotype‐matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.

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“…Indeed, over the last decade, the physical and chemical properties of the extracellular matrix have emerged as major players that tune those factordependent signaling pathways [3,4]. This regulation by the extracellular environment acts at various levels such as the adhesion-regulated formation of signaling platforms at the cell surface [5], the stimulation of endocytosis and vesicular trafficking [6][7][8], or the control of nuclear shuttling of specific transcription factors and chromatin remodelers to modulate gene expression [3,9,10].…”

Section: Introductionmentioning

confidence: 99%

Integrin-dependent YAP signaling requires LAMTOR1 mediated delivery of Src to the plasma membrane

Bouvard

Block

Brunner

et al. 2019

Preprint

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YAP signaling has emerged as an important signaling pathway involved in several normal and pathological processes. While main upstream effectors regulating its activity have been extensively studied, the interplay with other cellular processes has been far less analyzed. Here, we identified the LAMTOR complex as a new important regulator of YAP signaling. We uncovered that p18/LAMTOR1 is required for the recycling of Src on late endosomes to the cell periphery, and consequently to activate a signaling cascade that eventually controls YAP nuclear shuttling. Moreover, p18/LAMTOR1 positives late endosomes distribution is controlled by β1 integrins, extracellular matrix stiffness and cell contractility. This likely relies on the targeting of microtubules to β1 positive focal adhesion via ILK. Altogether our findings identify the late endosomal recycling pathway as a major regulator of YAP.3

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The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ

Cited by 253 publications

References 37 publications

The tumour microenvironment and immune milieu of cholangiocarcinoma

The tumour microenvironment and immune milieu of cholangiocarcinoma

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

Integrin-dependent YAP signaling requires LAMTOR1 mediated delivery of Src to the plasma membrane

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