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

doi:10.1016/j.celrep.2019.07.033

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

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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 language	English
Pages (from-to)	1785-1798.e6
Journal	Cell Reports
Volume	28
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2019.07.033
State	Published - 13 Aug 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

Funding

This work was supported by a grant from the Melanoma Research Alliance (MRA) to N. Erez, R.S.-F., and R.G. (the MRA-Saban Family Team Award) and by a grant from the German Research Foundation ( DFG PU 355/4-1 ) to N. Erez and T.P. N. Erez and R.S.-F. thank the Gail White and Ann and William Cohen Multidisciplinary Brain Cancer Research Program. N. Erez is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (starter grant agreement no. 637069 MetCAF ). T.P. is supported by the German Research Foundation ( DFG FOR2127 PU 355/5-1 ). R.S.-F. is also supported by the ERC under the European Union’s Seventh Framework Programme/ERC Consolidator grant agreement no. [617445]-PolyDorm . The authors would like to thank the Sackler Interdepartmental Core Facility (SICF) for help with imaging, FACS, and qPCR analyses. H.D. acknowledges the Foulkes Foundation MD/PhD fellowship . This work was supported by a grant from the Melanoma Research Alliance (MRA) to N. Erez, R.S.-F. and R.G. (the MRA-Saban Family Team Award) and by a grant from the German Research Foundation (DFG PU 355/4-1) to N. Erez and T.P. N. Erez and R.S.-F. thank the Gail White and Ann and William Cohen Multidisciplinary Brain Cancer Research Program. N. Erez is supported by funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (starter grant agreement no. 637069 MetCAF). T.P. is supported by the German Research Foundation (DFG FOR2127 PU 355/5-1). R.S.-F. is also supported by the ERC under the European Union's Seventh Framework Programme/ERC Consolidator grant agreement no. [617445]-PolyDorm. The authors would like to thank the Sackler Interdepartmental Core Facility (SICF) for help with imaging, FACS, and qPCR analyses. H.D. acknowledges the Foulkes Foundation MD/PhD fellowship. Conceptualization, H.D. M.A. and N. Erez; Methodology, H.D. M.A. and N. Erez; Investigation, H.D. M.A. N. Ershaid, M.Y. R.B. T.G.L. Z.H. S.P. A.S. and J.C.; Formal Analysis, O.S. L.M. N.C. and G.T.; Resources, M.Y. O.A. R.G. and R.S.-F.; Visualization, H.D. M.A. and N. Erez; Writing – Original Draft, H.D. M.A. and N. Erez; Writing – Review & Editing, H.D. M.A. and N. Erez; Project Administration, T.P. C.L. R.S.-F. and N. Erez; Supervision, N. Erez. All of the authors discussed the results and provided feedback on the manuscript. The authors declare no competing interests.

Funders	Funder number
Gail White and Ann and William Cohen Multidisciplinary Brain Cancer Research Program
Sackler Interdepartmental Core Facility
Melanoma Research Alliance
Horizon 2020 Framework Programme
Foulkes Foundation
European Commission
Deutsche Forschungsgemeinschaft	PU 355/4-1
Seventh Framework Programme	617445
Horizon 2020	FOR2127 PU 355/5-1, 637069

Keywords

CXCL10
CXCR3
astrocytes
brain metastasis
brain tropism
melanoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.07.033

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Cite this

Doron, H., Amer, M., Ershaid, N., Blazquez, R., Shani, O., Lahav, T. G., Cohen, N., Adler, O., Hakim, Z., Pozzi, S., Scomparin, A., Cohen, J., Yassin, M., Monteran, L., Grossman, R., Tsarfaty, G., Luxenburg, C., Satchi-Fainaro, R., Pukrop, T., & Erez, N. (2019). Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis. Cell Reports, 28(7), 1785-1798.e6. https://doi.org/10.1016/j.celrep.2019.07.033

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title = "Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis",

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.",

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Doron, H, Amer, M, Ershaid, N, Blazquez, R, Shani, O, Lahav, TG, Cohen, N, Adler, O, Hakim, Z, Pozzi, S, Scomparin, A, Cohen, J, Yassin, M, Monteran, L, Grossman, R, Tsarfaty, G, Luxenburg, C, Satchi-Fainaro, R, Pukrop, T & Erez, N 2019, 'Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis', Cell Reports, vol. 28, no. 7, pp. 1785-1798.e6. https://doi.org/10.1016/j.celrep.2019.07.033

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T1 - Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis

AU - Doron, Hila

AU - Amer, M.

AU - Ershaid, Nour

AU - Blazquez, Raquel

AU - Shani, O.

AU - Lahav, Tzlil Gener

AU - Cohen, Noam

AU - Adler, Omer

AU - Hakim, Zahi

AU - Pozzi, Sabina

AU - Scomparin, Anna

AU - Cohen, Jonathan

AU - Yassin, Muhammad

AU - Monteran, Lea

AU - Grossman, Rachel

AU - Tsarfaty, G.

AU - Luxenburg, Chen

AU - Satchi-Fainaro, R.

AU - Pukrop, Tobias

AU - Erez, Neta

PY - 2019/8/13

Y1 - 2019/8/13

N2 - 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.

AB - 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.

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KW - brain tropism

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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