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

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  • 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
  • Fernando Calvo
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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.

Original languageEnglish
Article number130
JournalNature Communications
Volume10
Issue number1
Pages (from-to)130
ISSN2041-1723
DOIs
Publication statusPublished - 1 Dec 2019

    Research areas

  • Adaptor Proteins, Signal Transducing/genetics, Animals, Cancer-Associated Fibroblasts/metabolism, Cell Line, Cells, Cultured, Chemokines, Gene Expression Profiling, Heat Shock Transcription Factors/genetics, Humans, Intercellular Signaling Peptides and Proteins/genetics, Intracellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-6/genetics, Membrane Proteins/genetics, Mice, Nude, Mice, Transgenic, Neoplasms/genetics, Phosphoproteins/genetics, Transcription Factors/genetics, Wnt Signaling Pathway/genetics, beta Catenin/genetics

ID: 56749526