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

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Title: Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts
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
Item Type: Journal Article
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.
Issue Date: 10-Jan-2019
Date of Acceptance: 10-Dec-2018
URI: http://hdl.handle.net/10044/1/67895
DOI: https://dx.doi.org/10.1038/s41467-018-07987-0
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 10
Issue: 1
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MICROARRAY DATA
BREAST-CANCER
EXPRESSION
METASTASIS
MICROENVIRONMENT
INHIBITION
INVASION
REVEALS
PROGRAM
PATHWAY
Adaptor Proteins, Signal Transducing
Animals
Cancer-Associated Fibroblasts
Cell Line
Cells, Cultured
Gene Expression Profiling
Heat Shock Transcription Factors
Humans
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Low Density Lipoprotein Receptor-Related Protein-6
Membrane Proteins
Mice, Nude
Mice, Transgenic
Neoplasms
Phosphoproteins
Transcription Factors
Wnt Signaling Pathway
beta Catenin
MD Multidisciplinary
Publication Status: Published
Open Access location: https://www.nature.com/articles/s41467-018-07987-0
Article Number: 130
Online Publication Date: 2019-01-10
Appears in Collections:Division of Surgery
Division of Cancer



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