CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization

Abstract

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke major phenotypic changes in lung fibroblasts to form a metastatic niche that supports malignant growth. Colonization of the lungs by cancer cells confers an inflammatory phenotype in associated fibroblasts, where IL-1α and IL-1β, secreted by breast cancer cells, induce CXCL9 and CXCL10 production in metastasis-associated fibroblasts via NF-κB signaling. These paracrine interactions fuel the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells with stem/progenitor cell properties and high tumor-initiating ability when cotransplanted with fibroblasts. CXCR3-expressing cancer cells show high JNK signaling that drives IL-1α/β expression. Thus, CXCR3 marks a population of breast cancer cells that induces CXCL9/10 production in fibroblast, but can also respond to and benefit from these chemokines.Importantly, disruption of this intercellular JNK-IL-1-CXCL9/10-CXCR3 axis significantly reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for this molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

Chemokine signaling in cancer-stroma communications

“…It functions through binding to the receptor CXCR3, which has two different isoforms of CXCR3A and CXCR3B (Ma et al 2015). Recent studies have demonstrated newfound roles in T cell activation and proliferation (Tan et al 2018; Gao et al 2020), angiogenesis (Ding et al 2016; Shen et al 2019), and fibroblast activation (Pein et al 2019).…”

“…Pein et al use a murine model of BC to demonstrate that JNK signaling from cancer cells induces IL1α, and IL1ß expression, which binds to IL1R in stromal fibroblasts, activating NFKß signaling and increasing fibroblast expression of CXCL9 and CCXL10 that feeds forward to bind to CCR3 on cancer cells. This generates a feedback loop that leads to a pro‐metastatic environment (Pein et al 2019).…”