Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis

Zhe Zhu; Pinar Mesci; Jean A. Bernatchez; Ryan C. Gimple; Xiuxing Wang; Simon T. Schafer; Hiromi I. Wettersten; Sungjun Beck; Alex E. Clark; Qiulian Wu; Briana C. Prager; Leo J.Y. Kim; Rekha Dhanwani; Sonia Sharma; Alexandra Garancher; Sara M. Weis; Stephen C. Mack; Priscilla D. Negraes; Cleber A. Trujillo; Luiz O. Penalva; Jing Feng; Zhou Lan; Rong Zhang; Alex W. Wessel; Sanjay Dhawan; Michael S. Diamond; Clark C. Chen; Robert J. Wechsler-Reya; Fred H. Gage; Hongzhen Hu; Jair L. Siqueira-Neto; Alysson R. Muotri; David A. Cheresh; Jeremy N. Rich

doi:10.1016/j.stem.2019.11.016

Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin α_vβ₅ Axis

Zhe Zhu, Pinar Mesci, Jean A. Bernatchez, Ryan C. Gimple, Xiuxing Wang, Simon T. Schafer, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Briana C. Prager, Leo J.Y. Kim, Rekha Dhanwani, Sonia Sharma, Alexandra Garancher, Sara M. Weis, Stephen C. Mack, Priscilla D. Negraes, Cleber A. Trujillo, Luiz O. PenalvaJing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Sanjay Dhawan, Michael S. Diamond, Clark C. Chen, Robert J. Wechsler-Reya, Fred H. Gage, Hongzhen Hu, Jair L. Siqueira-Neto, Alysson R. Muotri, David A. Cheresh, Jeremy N. Rich

Neurosurgery

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

109 Scopus citations

Abstract

Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin α_v (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin α_vβ₅. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin α_vβ₅ inhibition. Collectively, our studies identify integrin α_vβ₅ as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.

Original language	English (US)
Pages (from-to)	187-204.e10
Journal	Cell Stem Cell
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2019.11.016
State	Published - Feb 6 2020

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

Integrin αvβ5
Sox2
Zika
cancer stem cell
glioblastoma
glioblastoma stem cell
glioma
interferon
oncolytic virus
organoid

UN SDGs

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

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Zhu, Z., Mesci, P., Bernatchez, J. A., Gimple, R. C., Wang, X., Schafer, S. T., Wettersten, H. I., Beck, S., Clark, A. E., Wu, Q., Prager, B. C., Kim, L. J. Y., Dhanwani, R., Sharma, S., Garancher, A., Weis, S. M., Mack, S. C., Negraes, P. D., Trujillo, C. A., ... Rich, J. N. (2020). Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin α_vβ₅ Axis. Cell Stem Cell, 26(2), 187-204.e10. https://doi.org/10.1016/j.stem.2019.11.016

Zhu, Z, Mesci, P, Bernatchez, JA, Gimple, RC, Wang, X, Schafer, ST, Wettersten, HI, Beck, S, Clark, AE, Wu, Q, Prager, BC, Kim, LJY, Dhanwani, R, Sharma, S, Garancher, A, Weis, SM, Mack, SC, Negraes, PD, Trujillo, CA, Penalva, LO, Feng, J, Lan, Z, Zhang, R, Wessel, AW, Dhawan, S, Diamond, MS, Chen, CC, Wechsler-Reya, RJ, Gage, FH, Hu, H, Siqueira-Neto, JL, Muotri, AR, Cheresh, DA & Rich, JN 2020, 'Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin α_vβ₅ Axis', Cell Stem Cell, vol. 26, no. 2, pp. 187-204.e10. https://doi.org/10.1016/j.stem.2019.11.016

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abstract = "Zika virus (ZIKV) causes microcephaly by killing neural precursor cells (NPCs) and other brain cells. ZIKV also displays therapeutic oncolytic activity against glioblastoma (GBM) stem cells (GSCs). Here we demonstrate that ZIKV preferentially infected and killed GSCs and stem-like cells in medulloblastoma and ependymoma in a SOX2-dependent manner. Targeting SOX2 severely attenuated ZIKV infection, in contrast to AXL. As mechanisms of SOX2-mediated ZIKV infection, we identified inverse expression of antiviral interferon response genes (ISGs) and positive correlation with integrin αv (ITGAV). ZIKV infection was disrupted by genetic targeting of ITGAV or its binding partner ITGB5 and by an antibody specific for integrin αvβ5. ZIKV selectively eliminated GSCs from species-matched human mature cerebral organoids and GBM surgical specimens, which was reversed by integrin αvβ5 inhibition. Collectively, our studies identify integrin αvβ5 as a functional cancer stem cell marker essential for GBM maintenance and ZIKV infection, providing potential brain tumor therapy.",

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AU - Zhu, Zhe

AU - Mesci, Pinar

AU - Bernatchez, Jean A.

AU - Gimple, Ryan C.

AU - Wang, Xiuxing

AU - Schafer, Simon T.

AU - Wettersten, Hiromi I.

AU - Beck, Sungjun

AU - Clark, Alex E.

AU - Wu, Qiulian

AU - Prager, Briana C.

AU - Kim, Leo J.Y.

AU - Dhanwani, Rekha

AU - Sharma, Sonia

AU - Garancher, Alexandra

AU - Weis, Sara M.

AU - Mack, Stephen C.

AU - Negraes, Priscilla D.

AU - Trujillo, Cleber A.

AU - Penalva, Luiz O.

AU - Feng, Jing

AU - Lan, Zhou

AU - Zhang, Rong

AU - Wessel, Alex W.

AU - Dhawan, Sanjay

AU - Diamond, Michael S.

AU - Chen, Clark C.

AU - Wechsler-Reya, Robert J.

AU - Gage, Fred H.

AU - Hu, Hongzhen

AU - Siqueira-Neto, Jair L.

AU - Muotri, Alysson R.

AU - Cheresh, David A.

AU - Rich, Jeremy N.

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