Journal Article

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

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

2019

Overview

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. It is unclear how specific signalling pathways are coordinated to generate pathologically activated cancer associated fibroblasts (CAFs). Here, Ferrari et al show that stromal expression of Dickkopf-3 (DKK3) associates with aggressive tumours. DKK3 is a HSF-1 effector that activates β-catenin and YAP/TAZ, and DKK3-driven YAP/TAZ activation regulates the pro-tumorigenic behaviour of CAFs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 631/67/327 / 631/80/86 / Activation / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Animals / beta Catenin - genetics / beta Catenin - metabolism / Cancer / Cancer-Associated Fibroblasts - metabolism / Cell Line / Cell surface / Cells, Cultured / Chemokines / Extracellular matrix / Fibroblasts / Gene Expression Profiling / Heat Shock Transcription Factors - genetics / Heat Shock Transcription Factors - metabolism / HSF1 protein / Humanities and Social Sciences / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Intracellular Signaling Peptides and Proteins / Low Density Lipoprotein Receptor-Related Protein-6 - genetics / Low Density Lipoprotein Receptor-Related Protein-6 - metabolism / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice, Nude / Mice, Transgenic / multidisciplinary / Neoplasms - genetics / Neoplasms - metabolism / Neoplasms - pathology / Ovarian cancer / Phenotypes / Phosphoproteins - genetics / Phosphoproteins - metabolism / Science / Science (multidisciplinary) / Signal transduction / Signaling / Solid tumors / Trans-Activators / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Coactivator with PDZ-Binding Motif Proteins / Tumor microenvironment / Tumors / Wnt protein / Wnt Signaling Pathway - genetics / Yes-associated protein / β-Catenin