TY  - JOUR
AU  - Sjöberg, Elin
AU  - Meyrath, Max
AU  - Milde, Laura
AU  - Herrera, Mercedes
AU  - Lövrot, John
AU  - Hägerstrand, Daniel
AU  - Frings, Oliver
AU  - Bartish, Margarita
AU  - Rolny, Charlotte
AU  - Sonnhammer, Erik
AU  - Chevigné, Andy
AU  - Augsten, Martin
AU  - Östman, Arne
TI  - A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer.
JO  - Clinical cancer research
VL  - 25
IS  - 12
SN  - 1557-3265
CY  - Philadelphia, Pa. [u.a.]
PB  - AACR
M1  - DKFZ-2019-01718
SP  - 3702 - 3717
PY  - 2019
AB  - 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.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.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.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.See related commentary by Zhang et al., p. 3476.
KW  - CXCL14 protein, human (NLM Chemicals)
KW  - Chemokines, CXC (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30850359
DO  - DOI:10.1158/1078-0432.CCR-18-1294
UR  - https://inrepo02.dkfz.de/record/144169
ER  -