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Cited by 164Hippo pathway signaling and YAP/TAZWnt/β-catenin signaling in development and cancerCancer Cells and Metastasis

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

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Ferrari, Nicola, Ranftl, Romana, Chicherova, Ievgeniia, Slaven, Neil D., Moeendarbary, Emad, Farrugia, Aaron J., Lam, Maxine, Semiannikova, Maria +4 more·2019·Nature Communications
DOI 10.1038/s41467-018-07987-0PMC PMC6328607
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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.

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  • HSF1 is required for the generation of CAFs.

    “Heat shock factor 1 (HSF1), which responds in part to protein misfolding, is required for the generation of CAFs67,68.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [68]

    The Results section ('DKK3 is a HSF1 target gene upregulated in CAFs'; page unavailable) reports that silencing Hsf1 reduces DKK3 expression in existing CAFs and links HSF1 to aggressive CAF behaviours. The Introduction and Discussion connect this pathway to an activated CAF phenotype, but do not establish that HSF1 is required to generate CAFs. The Results also identify protein misfolding as a stress that can activate HSF1. (LLM, conf=0.84)

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Authors
Ferrari, N., Ranftl, R., Chicherova, I., Slaven, N. D., Moeendarbary, E., Farrugia, A. J., Lam, M., Semiannikova, M., Westergaard, M. C. W., Tchou, J., Magnani, L., & Calvo, F.
Affiliations
  • Institute of Cancer Research (GB)
  • Imperial College London (GB)
  • University College London (GB)
  • University of Copenhagen (DK)
  • Abramson Cancer Center (US)
Corresponding author
Calvo, Fernando
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-01-10
Volume
10
Issue
1
Pages
130-130
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-07987-0
PMC
PMC6328607
OpenAlex
W2911197932
Cited by
164
References
5
Citations by year
2026: 13 · 2025: 14 · 2024: 16 · 2023: 28 · 2022: 35 · 2021: 27 · 2020: 22 · 2019: 9
FWCI
12.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Cancer Research UK (C57744/A22057, 23110, 22057)
  • European Regional Development Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Dickkopf-3, HSF1, cancer-associated fibroblasts, tumor microenvironment, Wnt signaling, LRP6, β-catenin, extracellular matrix remodeling, tumor invasion, breast cancer, colorectal cancer, ovarian cancer, tumor aggressiveness
MeSH terms
Cancer-Associated Fibroblasts, Heat Shock Transcription Factors, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Animals, Cell Line, Cells, Cultured, Humans, Membrane Proteins, Mice, Nude, Mice, Transgenic, Neoplasms, Phosphoproteins, Transcription Factors, Trans-Activators, Chemokines, Gene Expression Profiling, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, beta Catenin, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6

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