Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis

Cell Rep. 2019 Aug 13;28(7):1785-1798.e6. doi: 10.1016/j.celrep.2019.07.033.


Melanoma is the deadliest skin cancer due to its high rate of metastasis, frequently to the brain. Brain metastases are incurable; therefore, understanding melanoma brain metastasis is of great clinical importance. We used a mouse model of spontaneous melanoma brain metastasis to study the interactions of melanomas with the brain microenvironment. We find that CXCL10 is upregulated in metastasis-associated astrocytes in mice and humans and is functionally important for the chemoattraction of melanoma cells. Moreover, CXCR3, the receptor for CXCL10, is upregulated in brain-tropic melanoma cells. Targeting melanoma expression of CXCR3 by nanoparticle-mediated siRNA delivery or by shRNA transduction inhibits melanoma cell migration and attenuates brain metastasis in vivo. These findings suggest that the instigation of pro-inflammatory signaling in astrocytes is hijacked by brain-metastasizing tumor cells to promote their metastatic capacity and that the CXCL10-CXCR3 axis may be a potential therapeutic target for the prevention of melanoma brain metastasis.

Keywords: CXCL10; CXCR3; astrocytes; brain metastasis; brain tropism; melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / immunology
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Brain Neoplasms / immunology
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / secondary*
  • Cell Movement
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism*
  • Disease Models, Animal*
  • Humans
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tumor Microenvironment


  • CXCL10 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL10
  • Receptors, CXCR3