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. 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

Research output: Contribution to journalArticle

7 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 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.

Original languageEnglish (US)
Pages (from-to)187-204.e10
JournalCell Stem Cell
Volume26
Issue number2
DOIs
StatePublished - Feb 6 2020

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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