Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts

Ferrari, Nicola; Ranftl, Romana; Chicherova, Ievgeniia; Slaven, Neil; Moeendarbary, Emad; Farrugia, Aaron J.; Lam, Maxine; Semiannikova, Maria; Westergaard, Marie Christine Wulff; Tchou, Julia; Magnani, Luca; Calvo, Fernando

doi:10.1038/s41467-018-07987-0

Cited by 132 publications

(128 citation statements)

References 48 publications

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“…Intriguingly, in contrast to those earlier studies (Azzolin et al, 2014;Ferrari et al, 2019), the authors now showed that LRP6…”

contrasting

confidence: 95%

“…The initial observation that LRP6 downregulation and Hippo activation co-occur upon nutrient starvation motivated the authors to address whether LRP6 regulates Hippo signaling. Several studies have already demonstrated that LRP6 inactivates Hippo signaling, at least in part through interfering with the interaction between YAP/TAZ and the b-catenin destruction complex (Azzolin et al, 2014;Ferrari et al, 2019). Using YAP phosphorylation, localization, and transcriptional activity as functional readouts for Hippo signaling output, Jeong et al confirmed that LRP6 is a negative regulator of the Hippo pathway and modulates Hippo signaling activity in response to nutrient levels.…”

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confidence: 99%

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LRP 6 lets Merlin go in times of nutrient scarcity

Wong

Verheyen

2020

EMBO Reports

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Cells take advantage of cross‐talk in signaling pathways to integrate diverse signals and produce coordinated responses. In this issue of EMBO Reports, Jeong et al discover that the Wnt co‐receptor, low‐density lipoprotein (LDL) receptor‐related protein LRP6, negatively regulates Hippo signaling by serving as a binding sink to sequester and inhibit Merlin, an activator of Hippo signaling (Jeong et al, 2020). This regulation is nutrient‐responsive, likely using LRP6 O‐GlcNAcylation as a molecular switch.

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“…Intriguingly, in contrast to those earlier studies (Azzolin et al, 2014;Ferrari et al, 2019), the authors now showed that LRP6…”

contrasting

confidence: 95%

mentioning

confidence: 99%

LRP 6 lets Merlin go in times of nutrient scarcity

Wong

Verheyen

2020

EMBO Reports

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“…Physiological stress is also another factor contributing to stromagenesis. Heat shock factor 1 (HSF1), which responds in part to protein misfolding, is required for the generation of CAFs 67,68 . Physiological and genomic stresses can also trigger changes in fibroblasts.…”

Section: What Is the Origin Of Cafs?mentioning

confidence: 99%

A framework for advancing our understanding of cancer-associated fibroblasts

et al. 2020

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Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment. Extracellular matrix (ECM).The structural network of secreted proteins and glycosaminoglycans that provides structure to tissue. Angiogenesis The formation of new blood vessels. Mesenchyme A type of tissue composed of loosely associated cells surrounded by extracellular matrix. Mesoderm one of three fundamental layers of tissue formed early in development and the predominant source of fibroblastic lineages.

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“…It has been proposed that the DKK3-Kremen-1 interaction may affect Wnt signaling (46). Nicola confirmed that Kremen-1, but not Lipoprotein receptor-related protein 6 (LRP6), immunoprecipitated with DKK3 in cancer-associated fibroblasts, and the mRNA levels of Kremen-1 were not altered after DKK3 silencing (47). In the present study, Kremen-1 did not show any change in expression during the same timeframe when DKK3 levels were observed to be reduced after ICH.…”

Section: Discussionmentioning

confidence: 93%

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

Yang

Nowrangi

Liang

et al. 2020

Preprint

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Background: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinﬂammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH. Methods: Male, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1β in the brain. Results: The expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated , at least partly, by the Kremen-1 and DVL-1 pathways. Conclusions: DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1 mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.

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Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts

Cited by 132 publications

References 48 publications

LRP 6 lets Merlin go in times of nutrient scarcity

LRP 6 lets Merlin go in times of nutrient scarcity

A framework for advancing our understanding of cancer-associated fibroblasts

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage

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