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

• Published in: Cell reports (Cambridge) Vol. 28; no. 7; pp. 1785 - 1798.e6
• Main Authors: Doron, Hila, Amer, Malak, Ershaid, Nour, Blazquez, Raquel, Shani, Ophir, Lahav, Tzlil Gener, Cohen, Noam, Adler, Omer, Hakim, Zahi, Pozzi, Sabina, Scomparin, Anna, Cohen, Jonathan, Yassin, Muhammad, Monteran, Lea, Grossman, Rachel, Tsarfaty, Galia, Luxenburg, Chen, Satchi-Fainaro, Ronit, Pukrop, Tobias, Erez, Neta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.08.2019; Elsevier
• Subjects: astrocytes; brain metastasis; brain tropism; CXCL10; CXCR3; melanoma; CXCL10; melanoma; brain metastasis; astrocytes; CXCR3; brain tropism
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •CXCL10 is upregulated in metastases-associated astrocytes in vivo•Astrocyte-derived CXCL10 enhances melanoma cell migration toward astrocytes•CXCR3, the receptor for CXCL10, is upregulated in brain-tropic melanoma cells•Targeting CXCR3 expression attenuates the formation of melanoma brain metastases 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.