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

Cell Stem Cell. 2020 Feb 6;26(2):187-204.e10. doi: 10.1016/j.stem.2019.11.016. Epub 2020 Jan 16.

Authors

Zhe Zhu¹, Pinar Mesci², Jean A Bernatchez³, Ryan C Gimple⁴, Xiuxing Wang¹, Simon T Schafer⁵, Hiromi I Wettersten⁶, Sungjun Beck³, Alex E Clark⁷, Qiulian Wu¹, Briana C Prager⁸, Leo J Y Kim⁹, Rekha Dhanwani¹⁰, Sonia Sharma¹⁰, Alexandra Garancher¹¹, Sara M Weis⁶, Stephen C Mack¹², Priscilla D Negraes¹³, Cleber A Trujillo¹³, Luiz O Penalva¹⁴, Jing Feng¹⁵, Zhou Lan¹⁵, Rong Zhang¹⁶, Alex W Wessel¹⁶, Sanjay Dhawan¹⁷, Michael S Diamond¹⁶, Clark C Chen¹⁷, Robert J Wechsler-Reya¹¹, Fred H Gage⁵, Hongzhen Hu¹⁵, Jair L Siqueira-Neto¹⁸, Alysson R Muotri¹⁹, David A Cheresh²⁰, Jeremy N Rich²¹

Affiliations

¹ Department of Medicine, Division of Regenerative Medicine, University of California School of Medicine, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
² Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Pediatrics, Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA; Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA.
³ Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92037, USA.
⁴ Department of Medicine, Division of Regenerative Medicine, University of California School of Medicine, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Case Western Reserve University Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
⁵ Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁶ Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Pathology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA.
⁷ Department of Cellular and Molecular Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92037, USA.
⁸ Department of Medicine, Division of Regenerative Medicine, University of California School of Medicine, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Case Western Reserve University Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
⁹ Department of Medicine, Division of Regenerative Medicine, University of California School of Medicine, San Diego, La Jolla, CA 92037, USA; Case Western Reserve University Medical Scientist Training Program, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
¹⁰ La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
¹¹ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
¹² Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
¹³ Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Pediatrics, Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA.
¹⁴ Children's Cancer Research Institute - UTHSCSA, San Antonio, TX 78229, USA.
¹⁵ Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine in St. Louis, St. Louis, MO 63130, USA.
¹⁶ Departments of Medicine, Molecular Microbiology, Pathology, and Immunology and The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63130, USA.
¹⁷ Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁸ Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA. Electronic address: jairlage@ucsd.edu.
¹⁹ Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Pediatrics, Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA. Electronic address: muotri@ucsd.edu.
²⁰ Department of Pathology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address: dcheresh@ucsd.edu.
²¹ Department of Medicine, Division of Regenerative Medicine, University of California School of Medicine, San Diego, La Jolla, CA 92037, USA; Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA. Electronic address: drjeremyrich@gmail.com.

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.

Keywords: Integrin αvβ5; Sox2; Zika; cancer stem cell; glioblastoma; glioblastoma stem cell; glioma; interferon; oncolytic virus; organoid.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Glioblastoma*
Humans
Neural Stem Cells*
Receptors, Vitronectin
SOXB1 Transcription Factors / genetics
Zika Virus Infection*
Zika Virus*

Substances

Receptors, Vitronectin
SOX2 protein, human
SOXB1 Transcription Factors
integrin alphaVbeta5

Abstract

Publication types

MeSH terms

Substances

Grants and funding