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

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Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-01-16 , DOI: 10.1016/j.stem.2019.11.016
Zhe Zhu ₁ , Pinar Mesci ₂ , Jean A Bernatchez ₃ , Ryan C Gimple ₄ , Xiuxing Wang ₁ , Simon T Schafer ₅ , Hiromi I Wettersten ₆ , Sungjun Beck ₃ , Alex E Clark ₇ , Qiulian Wu ₁ , Briana C Prager ₈ , Leo J Y Kim ₉ , Rekha Dhanwani ₁₀ , Sonia Sharma ₁₀ , Alexandra Garancher ₁₁ , Sara M Weis ₆ , Stephen C Mack ₁₂ , Priscilla D Negraes ₁₃ , Cleber A Trujillo ₁₃ , Luiz O Penalva ₁₄ , Jing Feng ₁₅ , Zhou Lan ₁₅ , Rong Zhang ₁₆ , Alex W Wessel ₁₆ , Sanjay Dhawan ₁₇ , Michael S Diamond ₁₆ , Clark C Chen ₁₇ , Robert J Wechsler-Reya ₁₁ , Fred H Gage ₅ , Hongzhen Hu ₁₅ , Jair L Siqueira-Neto ₁₈ , Alysson R Muotri ₁₃ , David A Cheresh ₁₉ , Jeremy N Rich ₂₀

Affiliation

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.
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.
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.
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.
Laboratory of Genetics, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
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.
Department of Cellular and Molecular Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92037, USA.
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.
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.
La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
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.
Children's Cancer Research Institute - UTHSCSA, San Antonio, TX 78229, USA.
Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine in St. Louis, St. Louis, MO 63130, USA.
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.
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California, San Diego, La Jolla, CA 92307, USA.
Department of Pathology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA.
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.

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.

中文翻译：

Zika 病毒通过 SOX2-整合素 αvβ5 轴靶向胶质母细胞瘤干细胞。

寨卡病毒 (ZIKV) 通过杀死神经前体细胞 (NPC) 和其他脑细胞导致小头畸形。ZIKV 还显示出针对胶质母细胞瘤 (GBM) 干细胞 (GSC) 的治疗性溶瘤活性。在这里，我们证明 ZIKV 以 SOX2 依赖性方式优先感染和杀死髓母细胞瘤和室管膜瘤中的 GSC 和干细胞样细胞。与 AXL 相比，靶向 SOX2 可严重减弱 ZIKV 感染。作为 SOX2 介导的 ZIKV 感染的机制，我们确定了抗病毒干扰素反应基因 (ISG) 的反向表达以及与整合素 αv (ITGAV) 的正相关。ZIKV 感染被 ITGAV 或其结合伙伴 ITGB5 的基因靶向和整合素 αvβ5 特异性抗体破坏。ZIKV 从物种匹配的人类成熟脑类器官和 GBM 手术标本中选择性地消除 GSC，这被整合素αvβ5抑制逆转。总的来说，我们的研究将整合素 αvβ5 确定为对 GBM 维持和 ZIKV 感染至关重要的功能性癌症干细胞标志物，从而提供潜在的脑肿瘤治疗。

更新日期：2020-01-17

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