Zika virus selectively kills aggressive human embryonal CNS tumor cells in vitro and in vivo

Carolini Kaid, Ernesto Goulart, Luiz C Caires-Júnior, Bruno H S Araujo, Alessandra Soares-Schanoski, Heloisa M S Bueno, Kayque A Telles-Silva, Renato M Astray, Amanda F Assoni, Antônio F R Júnior, Daniella C Ventini, Ana L P Puglia, Roselane P Gomes, Mayana Zatz, Oswaldo K Okamoto

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells (NPC) during early development. Here we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR. Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and provide mechanistic insights regarding its oncolytic effects.