Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models

Author(s)

Ferreira, Rodolfo Sanches ; Jandrey, Elisa Helena Farias ; Granha, Isabela ; Endo, Alice Kei ; Ferreira, Raiane Oliveira ; Araujo, Bruno Henrique Silva ; Zatz, Mayana ; Okamoto, Oswaldo Keith

• Document type: Journal article
• Source: Viruses-Basel; v. 16, n. 11, p. 14-pg., 2024-11-01.

Abstract

Central nervous system (CNS) cancers are responsible for high rates of morbidity and mortality worldwide. Malignant CNS tumors such as adult Glioblastoma (GBM) and pediatric embryonal CNS tumors such as medulloblastoma (MED) and atypical teratoid rhabdoid tumors (ATRT) present relevant therapeutic challenges due to the lack of response to classic treatment regimens with radio and chemotherapy. Recent findings on the Zika virus' (ZIKV) ability to infect and kill CNS neoplastic cells draw attention to the virus' oncolytic potential. Studies demonstrating the safety of using ZIKV for treating malignant CNS tumors, enabling the translation of this approach to clinical trials, are scarce in the literature. Here we developed a co-culture model of mature human cerebral organoids assembled with GBM, MED or ATRT tumor cells and used these assembloids to test ZIKV oncolytic effect, replication potential and preferential targeting between normal and cancer cells. Our hybrid co-culture models allowed the tracking of tumor cell growth and invasion in cerebral organoids. ZIKV replication and ensuing accumulation in the culture medium was higher in organoids co-cultured with tumor cells than in isolated control organoids without tumor cells. ZIKV infection led to a significant reduction in tumor cell proportion in organoids with GBM and MED cells, but not with ATRT. Tumoroids (3D cultures of tumor cells alone) were efficiently infected by ZIKV. Interestingly, ZIKV rapidly replicated in GBM, MED, and ATRT tumoroids reaching significantly higher viral RNA accumulation levels than co-cultures. Moreover, ZIKV infection reduced viable cells number in MED and ATRT tumoroids but not in GBM tumoroids. Altogether, our findings indicate that ZIKV has greater replication rates in aggressive CNS tumor cells than in normal human cells comprising cerebral organoids. However, such higher ZIKV replication in tumor cells does not necessarily parallels oncolytic effects, suggesting cellular intrinsic and extrinsic factors mediating tumor cell death by ZIKV. (AU)

• FAPESP's process: 19/27784-8 - Study of oncolytic virus on an in vitro model of glioblastoma developed in brain organoid
• Grantee: Rodolfo Sanches Ferreira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 23/02209-6 - Analysis of the oncolytic effect of ZIKV on temozolomide-resistant glioblastoma cells
• Grantee: Isabela Fonseca de Oliveira Granha
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/14109-8 - Study of the oncolytic effect of Zika Virus on cells in the central nervous system tumor micro-environment
• Grantee: Raiane de Oliveira Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/04323-5 - Evaluation of EZH2 expression and activity as factors of cellular susceptibility to Zika Virus infection in embryonic central nervous system tumors
• Grantee: Elisa Helena Farias Jandrey
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC