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
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Adaptor Proteins, Signal Transducing
Gene Expression Profiling
Low Density Lipoprotein Receptor-Related Protein-6
Wnt Signaling Pathway
Heat Shock Transcription Factors
License start date
Nature communications, 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.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Xiong, S; Lorenzen, K; Couzens, AL; Templeton, CM; Rajendran, D; Mao, DYL; Juang, Y-C; Chiovitti, D; Kurinov, I; Guettler, S; Gingras, A-C; Sicheri, F (2018-08)The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase ...
Multiparametric Analysis of Cell Shape Demonstrates that β-PIX Directly Couples YAP Activation to Extracellular Matrix Adhesion. Sero, JE; Bakal, C (2017-01-05)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 ...
Faull, SV; Lau, AMC; Martens, C; Ahdash, Z; Hansen, K; Yebenes, H; Schmidt, C; Beuron, F; Cronin, NB; Morris, EP; Politis, A (2019-08-23)Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures ...