Abstract :
[en] Purpose: Fibroblasts expressing the orphan chemokine
CXCL14 have been previously shown to associate with poor
breast cancer prognosis and promote cancer growth. This study
explores the mechanism underlying the poor survival associations
of stromal CXCL14.
Experimental Design: Tumor cell epithelial-to-mesenchymal
transition (EMT), invasion, and metastasis were studied in in
vitro and in vivo models together with fibroblasts overexpressing
CXCL14. An approach for CXCL14 receptor identification
included loss-of-function studies followed by molecular and
functional endpoints. The clinical relevance was further
explored in publicly available gene expression datasets.
Results: CXCL14 fibroblasts stimulated breast cancer EMT,
migration, and invasion in breast cancer cells and in a xenograft
model. Furthermore, tumor cells primed by CXCL14
fibroblasts displayed enhanced lung colonization after tail-vein
injection. By loss-of function experiments, the atypical
G-protein–coupled receptor ACKR2 was identified to mediate
CXCL14-stimulated responses. Downregulation of ACKR2, or
CXCL14-induced NOS1, attenuated the pro-EMT and migratory
capacity. CXCL14/ACKR2 expression correlated with EMT
and survival in gene expression datasets.
Conclusions: Collectively, the findings imply an autocrine
fibroblast CXCL14/ACKR2 pathway as a clinically relevant stimulator
of EMT, tumor cell invasion, and metastasis. The study
also identifies ACKR2 as a novel mediator for CXCL14 function
and thereby defines a pathway with drug target potential.
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