A novel ACKR2-Dependent role of fibroblast-derived CXCL14 in epithelial-to-mesenchymal transition and metastasis of breast cancer

Elin Sjöberg, Max Meyrath, Laura Milde, Mercedes Herrera, John Lövrot, Daniel Hägerstrand, Oliver Frings, Margarita Bartish, Charlotte Rolny, Erik Sonnhammer, Andy Chevigné, Martin Augsten, Arne Östman*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3702-3717
Number of pages16
JournalClinical Cancer Research
Volume25
Issue number12
DOIs
Publication statusPublished - 15 Jun 2019

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