Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs

Nat Commun. 2020 Mar 20;11(1):1494. doi: 10.1038/s41467-020-15188-x.


Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1β secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling 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, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/β expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL9 / metabolism
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-1alpha / metabolism
  • Interleukin-1beta / metabolism
  • Lung / metabolism*
  • Lung / pathology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Neoplasm Metastasis*
  • Receptors, CXCR3 / metabolism
  • Signal Transduction
  • Transcriptome
  • Transplantation, Heterologous
  • Tumor Microenvironment / physiology*


  • CXCL9 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Chemokine CXCL9
  • IL1B protein, human
  • Interleukin-1alpha
  • Interleukin-1beta
  • NF-kappa B
  • Receptors, CXCR3