Journal
CELL REPORTS
Volume 28, Issue 7, Pages 1785-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.033
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Funding
- Melanoma Research Alliance (MRA)
- German Research Foundation [DFG PU 355/4-1, DFG FOR2127 PU 355/5-1]
- European Research Council (ERC) under the European Union [637069 MetCAF]
- ERC under the European Union's Seventh Framework Programme/ERC Consolidator grant [617445]
- Foulkes Foundation MD/PhD fellowship
- European Research Council (ERC) [617445] Funding Source: European Research Council (ERC)
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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.
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