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

Author

Listed:
  • Nicola Ferrari

    (The Institute of Cancer Research
    Astex Pharmaceuticals)

  • 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
    Massachusetts Institute of Technology, Cambridge)

  • 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
    Instituto de Biomedicina y Biotecnologia de Cantabria)

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.

Suggested Citation

  • 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 , 2019. "Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07987-0
    DOI: 10.1038/s41467-018-07987-0
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    Cited by:

    1. Lee Shaashua & Aviad Ben-Shmuel & Meirav Pevsner-Fischer & Gil Friedman & Oshrat Levi-Galibov & Subhiksha Nandakumar & Debra Barki & Reinat Nevo & Lauren E. Brown & Wenhan Zhang & Yaniv Stein & Chen L, 2022. "BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.

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