Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
View/ Open
Date
2019-01-10Author
Ferrari, N
Ranftl, R
Chicherova, I
Slaven, ND
Moeendarbary, E
Farrugia, AJ
Lam, M
Semiannikova, M
Westergaard, MCW
Tchou, J
Magnani, L
Calvo, F
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cells, Cultured
Cell Line
Animals
Mice, Transgenic
Humans
Mice, Nude
Neoplasms
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Adaptor Proteins, Signal Transducing
Trans-Activators
Membrane Proteins
Phosphoproteins
Transcription Factors
Chemokines
Gene Expression Profiling
beta Catenin
Low Density Lipoprotein Receptor-Related Protein-6
Wnt Signaling Pathway
Cancer-Associated Fibroblasts
Heat Shock Transcription Factors
Research team
Tumour Microenvironment
Translational Oncogenomics
Language
eng
Date accepted
2018-12-10
License start date
2019-01-10
Citation
Nature communications, 2019, 10 (1), pp. 130 - ?
Publisher
NATURE PUBLISHING GROUP
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
Related items
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; et al. (CELL PRESS, 2018-08-07)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 (CELL PRESS, 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 ... -
MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis.
Xu, D; Yao, M; Wang, Y; Yuan, L; Hoeck, JD; et al. (PUBLIC LIBRARY SCIENCE, 2018-12-01)Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated ...