TY - JOUR
T1 - A novel ACKR2-Dependent role of fibroblast-derived CXCL14 in epithelial-to-mesenchymal transition and metastasis of breast cancer
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
N1 - Funding Information:
Members of A. Ostman's€ group are acknowledged for support throughout the studies. Studies were supported by grants from the Swedish Cancer Society, BRECT, the LinnéSTARGET grant from Swedish Research Council and the KI/AZ-collaborative initiative, the Luxembourg Institute of Health (LIH) MESR (grants 20160116 and 20170113), and the Luxembourg National Research Fund PhD fellows (grants AFR-3004509 and INTER/FWO "Nanokine" - grant 15/10358798). Technical support was provided by the histo-pathology unit of Cancer Centrum Karolinska. Animal experiments benefited from the expertise of the MTC animal facility.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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. ExperimentalDesign: 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 tailvein 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.
AB - 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. ExperimentalDesign: 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 tailvein 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.
UR - http://www.scopus.com/inward/record.url?scp=85067464467&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-1294
DO - 10.1158/1078-0432.CCR-18-1294
M3 - Article
C2 - 30850359
AN - SCOPUS:85067464467
SN - 1078-0432
VL - 25
SP - 3702
EP - 3717
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -