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

Nicola Ferrari, Romana Ranftl, Ievgeniia Chicherova, Neil D. Slaven, Emad Moeendarbary, Aaron J. Farrugia, Maxine Lam, Maria Semiannikova, Marie C. W. Westergaard, Julia Tchou, Luca Magnani and Fernando Calvo ()
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Nicola Ferrari: The Institute of Cancer Research
Romana Ranftl: The Institute of Cancer Research
Ievgeniia Chicherova: The Institute of Cancer Research
Neil D. Slaven: Imperial College London
Emad Moeendarbary: University College London
Aaron J. Farrugia: The Institute of Cancer Research
Maxine Lam: The Institute of Cancer Research
Maria Semiannikova: The Institute of Cancer Research
Marie C. W. Westergaard: University of Copenhagen
Julia Tchou: University of Pennsylvania
Luca Magnani: Imperial College London
Fernando Calvo: The Institute of Cancer Research

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.

Date: 2019
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DOI: 10.1038/s41467-018-07987-0

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