TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells

Elster, Dana; Tollot, Marie; Schlegelmilch, Karin; Ori, Alessandro; Rosenwald, Andreas; Sahai, Erik; Eyß, Björn von

doi:10.1038/s41467-018-05370-7

Cited by 72 publications

(76 citation statements)

References 45 publications

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“…In contrast, a YAP-independent mechanotransduction pathway was recently proposed to drive breast cancer progression ( 59 ). Moreover, recent studies implicate YAP as a tumor suppressor during in vivo breast cancer progression ( [60][61][62] ). In our study, we show that a subset of cells, at the periphery of the tumor, can deform to the point of generating NE ruptures and DNA damage and that this phenomenon, which in some of the systems we studied is dependent on the nuclease TREX1, is responsible for an increase in cell invasiveness.…”

Section: Discussionmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. Main text:( 16,21-23 ), and corresponds to cells squeezing each other as they move. These deformed nuclei were also more often positive for γH2AX than less deformed ones, and in general displayed more intense γH2AX staining than nuclei in the bulk of the tumor ( Fig. 1A-C). This suggests that, at the in situ stage of human breast carcinoma, strands of motile cells at the periphery of the tumor exhibit pronounced nuclear deformation, associated with elevated DNA damage.We then investigated a xenograft mouse model based on the intraductal (intra-nipple) injection of transformed human breast MCF10DCIS.com (DCIS) cells, which are derived from the nontransformed MCF10A cell line, and that recapitulates the transition from in situ to invasive stages of breast cancer progression ( 17,24 ). Tumors at various stages were analyzed. In situ tumors (further divided in early and advanced stages based on the continuity of the myoepithelial layer) are characterized by a myoepithelial layer (stained with smooth muscle actin) surrounding human xenograft cells that were identified by the human-specific KU70 antibody. In order to verify whether human tumor cells similarly experience DNA damage in the tumor xenografts, tumor sections were stained with γH2AX ( Fig. 1E-F, Fig. S1A). Similar to human tumor specimens, xenograft tumors displayed numerous deformed nuclei, mostly found at the periphery of the tumor mass, close to the myoepithelium, especially in ducts inflated with large tumors (Fig. 1E-F), and enriched in regions showing micro-invasive foci. Strikingly, these regions were also enriched in γH2AX-positive nuclei (Fig. 1F). Since γH2AX is also known...

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Section: Discussionmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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“…Diese Ergebnisse legten also nahe, dass es in Brustkrebs in der Tat von therapeutischem Nutzen sein kann, die YAP-Aktivität in Tumorzellen wieder zu erhöhen. Zu diesem Zweck hat unser Labor einen genomweiten CRISPR-Screen durchgeführt, und wir konnten den Transkriptionsfaktor Tricho-rhino-phalangeales Syndrom 1 (TRPS1) als potenten Repressor der transkriptionellen Aktivität von YAP identifi zieren [9].…”

Section: Wissenschaftunclassified

“…2B). Dies wirkt sich wiederum auf die Interaktion von TRPS1gebundenen Enhancern mit ihren Zielpromotoren aus, sodass die TRPS1-Bindung zu einer schwächeren Enhancer-Promotor-Interaktion und schließlich zur Repression von YAP-Zielgenen führt [9].…”

Section: Trps1 Als Neuer Repressor Der Transkriptionellen Aktivität Vunclassified

Der Hippo-Signalweg in der Regeneration und im Krebs

2020

Self Cite

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aktoren von Bedeutung, da diese Faktoren für den Hauptanteil der transkriptionellen Aktivität von YAP/TAZ verantwortlich sind. Der Hippo-Signalweg kann durch eine Vielzahl von Stimuli aktiviert und moduliert werden, wobei die genaue Entschlüsselung dieser vorgeschalteten Mechanismen noch Gegenstand intensiver Forschung ist. YAP/TAZ in der Regeneration Aufgrund des starken Wachstumsphänotyps nach deregulierter Aktivität des Hippo-Signalweges in D. melanogaster haben sich zunächst viele Forschungsarbeiten auf die Rolle dieses Signalweges in der Tumorgenese MARIE TOLLOT, ANITA CINDRIC VRANESIC, BJÖRN VON EYSS LEIBNIZ-INSTITUT FÜR ALTERNSFORSCHUNG-FRITZ-LIPMANN-INSTITUT (FLI), JENA The Hippo signalling pathway is a highly conserved regulator of tissue homeostasis and regeneration. Numerous studies in mouse and human have associated aberrant Hippo pathway activity with cancer development. YAP-the main downstream Hippo pathway effectorcan function both as an oncoprotein and a tumor suppressor depending on the cellular context. We recently identifi ed TRPS1 as a novel repressor of YAP activity.

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“…In addition, YAP1 can translocate to the nucleus and associate with tumor suppressor p73, resulting in apoptosis through transcriptional activation of the proapoptotic gene puma [ 46 ]. Another explanation for the tumor-suppressive role of YAP is that deregulated TAZ/YAP activity in BC cells induces an anti-tumorigenic immune surveillance response, ultimately leading to the eradication of tumor cells so BC cells have to restrain YAP activity consequently [ 54 , 55 ]. Moreover, studies reported that YAP can bind and signal through anti-apoptotic protein (delta)ΔNp63 isoform to protect cancer cells from DNA damage.…”

Section: The Roles Of the Hippo Pathway In Breast Cancermentioning

confidence: 99%

Targeting the Hippo Pathway for Breast Cancer Therapy

Yang

2018

Cancers

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Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy.

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TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells

Cited by 72 publications

References 45 publications

Compromised nuclear envelope integrity drives tumor cell invasion

Compromised nuclear envelope integrity drives tumor cell invasion

Der Hippo-Signalweg in der Regeneration und im Krebs

Targeting the Hippo Pathway for Breast Cancer Therapy

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