TY - JOUR
T1 - Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts
AU - Ferrari, Nicola
AU - Ranftl, Romana
AU - Chicherova, Ievgeniia
AU - Slaven, Neil D.
AU - Moeendarbary, Emad
AU - Farrugia, Aaron J.
AU - Lam, Maxine
AU - Semiannikova, Maria
AU - Westergaard, Marie C.W.
AU - Tchou, Julia
AU - Magnani, Luca
AU - Calvo, Fernando
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Animals
KW - Cancer-Associated Fibroblasts/metabolism
KW - Cell Line
KW - Cells, Cultured
KW - Chemokines
KW - Gene Expression Profiling
KW - Heat Shock Transcription Factors/genetics
KW - Humans
KW - Intercellular Signaling Peptides and Proteins/genetics
KW - Intracellular Signaling Peptides and Proteins
KW - Low Density Lipoprotein Receptor-Related Protein-6/genetics
KW - Membrane Proteins/genetics
KW - Mice, Nude
KW - Mice, Transgenic
KW - Neoplasms/genetics
KW - Phosphoproteins/genetics
KW - Transcription Factors/genetics
KW - Wnt Signaling Pathway/genetics
KW - beta Catenin/genetics
UR - http://www.scopus.com/inward/record.url?scp=85059829263&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-07987-0
DO - 10.1038/s41467-018-07987-0
M3 - Journal article
C2 - 30631061
AN - SCOPUS:85059829263
SN - 2041-1722
VL - 10
SP - 130
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 130
ER -