Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
MetadataShow full item record
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.
Version of record
Adaptor Proteins, Signal Transducing
Gene Expression Profiling
Heat Shock Transcription Factors
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Low Density Lipoprotein Receptor-Related Protein-6
Wnt Signaling Pathway
License start date
Nat Commun, 2019, 10 (1), pp. 130 - ?
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
Showing items related by title, author, creator and subject.
Multiparametric Analysis of Cell Shape Demonstrates that β-PIX Directly Couples YAP Activation to Extracellular Matrix Adhesion. Sero, JE; Bakal, C (2017-01-25)Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control ...
Jaco, I; Annibaldi, A; Lalaoui, N; Wilson, R; Tenev, T; Laurien, L; Kim, C; Jamal, K; Wicky John, S; Liccardi, G; Chau, D; Murphy, JM; Brumatti, G; Feltham, R; Pasparakis, M; Silke, J; Meier, P (2017-06-01)TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase ...
Annibaldi, A; Wicky John, S; Vanden Berghe, T; Swatek, KN; Ruan, J; Liccardi, G; Bianchi, K; Elliott, PR; Choi, SM; Van Coillie, S; Bertin, J; Wu, H; Komander, D; Vandenabeele, P; Silke, J; Meier, P (2018-02-15)Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains ...