Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts.
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Embargo End Date
ICR Authors
Authors
Ferrari, N
Ranftl, R
Chicherova, I
Slaven, ND
Moeendarbary, E
Farrugia, AJ
Lam, M
Semiannikova, M
Westergaard, MCW
Tchou, J
Magnani, L
Calvo, F
Ranftl, R
Chicherova, I
Slaven, ND
Moeendarbary, E
Farrugia, AJ
Lam, M
Semiannikova, M
Westergaard, MCW
Tchou, J
Magnani, L
Calvo, F
Document Type
Journal Article
Date
2019-01-10
Date Accepted
2018-12-10
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.
Citation
Nature communications, 2019, 10 (1), pp. 130 - ?
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Tumour Microenvironment
Translational Oncogenomics
Translational Oncogenomics