Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models
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 c...
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| author | Rodolfo Sanches Ferreira Elisa Helena Farias Jandrey Isabela Granha Alice Kei Endo Raiane Oliveira Ferreira Bruno Henrique Silva Araujo Mayana Zatz Oswaldo Keith Okamoto |
| author_facet | Rodolfo Sanches Ferreira Elisa Helena Farias Jandrey Isabela Granha Alice Kei Endo Raiane Oliveira Ferreira Bruno Henrique Silva Araujo Mayana Zatz Oswaldo Keith Okamoto |
| author_sort | Rodolfo Sanches Ferreira |
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| description | 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. |
| format | Article |
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| institution | OA Journals |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-11-01 |
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| series | Viruses |
| spelling | doaj-art-bf557c1bc9dd486688cc326f5ca3c8ef2025-08-20T01:54:08ZengMDPI AGViruses1999-49152024-11-011611176410.3390/v16111764Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid ModelsRodolfo Sanches Ferreira0Elisa Helena Farias Jandrey1Isabela Granha2Alice Kei Endo3Raiane Oliveira Ferreira4Bruno Henrique Silva Araujo5Mayana Zatz6Oswaldo Keith Okamoto7Human Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilBrazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Rua Giuseppe Máximo Scolfaro, No. 10.000, Campinas 13083-970, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilHuman Genome and Stem Cell Research Center (CEGH-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Cidade Universitária, São Paulo 05508-090, SP, BrazilCentral 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.https://www.mdpi.com/1999-4915/16/11/1764cancerZika virusbrain organoidscentral nervous system tumorsglioblastomamedulloblastoma |
| spellingShingle | Rodolfo Sanches Ferreira Elisa Helena Farias Jandrey Isabela Granha Alice Kei Endo Raiane Oliveira Ferreira Bruno Henrique Silva Araujo Mayana Zatz Oswaldo Keith Okamoto Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models Viruses cancer Zika virus brain organoids central nervous system tumors glioblastoma medulloblastoma |
| title | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models |
| title_full | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models |
| title_fullStr | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models |
| title_full_unstemmed | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models |
| title_short | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models |
| title_sort | differential replication and oncolytic effects of zika virus in aggressive cns tumor cells insights from organoid and tumoroid models |
| topic | cancer Zika virus brain organoids central nervous system tumors glioblastoma medulloblastoma |
| url | https://www.mdpi.com/1999-4915/16/11/1764 |
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