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

Hila Doron, M. Amer, Nour Ershaid, Raquel Blazquez, O. Shani, Tzlil Gener Lahav, Noam Cohen, Omer Adler, Zahi Hakim, Sabina Pozzi, Anna Scomparin, Jonathan Cohen, Muhammad Yassin, Lea Monteran, Rachel Grossman, G. Tsarfaty, Chen Luxenburg, R. Satchi-Fainaro, Tobias Pukrop, Neta Erez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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. Melanoma brain metastases are incurable. Doron et al. find that astrocyte-secreted CXCL10 is functional in melanoma chemoattraction to the brain. CXCR3, the CXCL10 receptor, is upregulated in brain-seeking melanoma cells. Silencing CXCR3 expression attenuates brain metastasis, suggesting that the CXCL10-CXCR3 axis may be a therapeutic target for melanoma brain metastasis.

Original languageEnglish
Pages (from-to)1785-1798.e6
JournalCell Reports
Volume28
Issue number7
DOIs
StatePublished - 13 Aug 2019

Keywords

  • CXCL10
  • CXCR3
  • astrocytes
  • brain metastasis
  • brain tropism
  • melanoma

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