MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma
Abstract Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficien...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-06-01
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| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-022-00409-3 |
| _version_ | 1818249884775481344 |
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| author | Maria K. E. Blixt Minas Hellsand Dardan Konjusha Hanzhao Zhang Sonya Stenfelt Mikael Åkesson Nima Rafati Tatsiana Tararuk Gustav Stålhammar Charlotta All-Eriksson Henrik Ring Finn Hallböök |
| author_facet | Maria K. E. Blixt Minas Hellsand Dardan Konjusha Hanzhao Zhang Sonya Stenfelt Mikael Åkesson Nima Rafati Tatsiana Tararuk Gustav Stålhammar Charlotta All-Eriksson Henrik Ring Finn Hallböök |
| author_sort | Maria K. E. Blixt |
| collection | DOAJ |
| description | Abstract Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of RB1 loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We used the chicken retina, a well-established model for studying retinal neurogenesis, and established human embryonic stem cell-derived retinal organoids as model systems. We over-expressed MYCN by electroporation of piggyBac genome-integrating expression vectors. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human organoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7–9 weeks in chicken. Cells expressing MYCN could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for cone progenitors. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone/horizontal cell lineage mediates the cancer phenotype. |
| first_indexed | 2024-12-12T15:43:35Z |
| format | Article |
| id | doaj.art-2976fda0764242cf9f06f74e45132fbb |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-12-12T15:43:35Z |
| publishDate | 2022-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-2976fda0764242cf9f06f74e45132fbb2022-12-22T00:19:50ZengNature Publishing GroupOncogenesis2157-90242022-06-0111111310.1038/s41389-022-00409-3MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastomaMaria K. E. Blixt0Minas Hellsand1Dardan Konjusha2Hanzhao Zhang3Sonya Stenfelt4Mikael Åkesson5Nima Rafati6Tatsiana Tararuk7Gustav Stålhammar8Charlotta All-Eriksson9Henrik Ring10Finn Hallböök11Department of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityNational Bioinformatics Infrastructure Sweden, Uppsala University, SciLifeLab, Department of Medical Biochemistry and MicrobiologyDepartment of Immunology, Genetics, and Pathology, Uppsala UniversitySt. Erik Eye Hospital, Department of Clinical Neuroscience, Karolinska InstituteSt. Erik Eye Hospital, Department of Clinical Neuroscience, Karolinska InstituteDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityDepartment of Immunology, Genetics, and Pathology, Uppsala UniversityAbstract Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of RB1 loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We used the chicken retina, a well-established model for studying retinal neurogenesis, and established human embryonic stem cell-derived retinal organoids as model systems. We over-expressed MYCN by electroporation of piggyBac genome-integrating expression vectors. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human organoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7–9 weeks in chicken. Cells expressing MYCN could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for cone progenitors. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone/horizontal cell lineage mediates the cancer phenotype.https://doi.org/10.1038/s41389-022-00409-3 |
| spellingShingle | Maria K. E. Blixt Minas Hellsand Dardan Konjusha Hanzhao Zhang Sonya Stenfelt Mikael Åkesson Nima Rafati Tatsiana Tararuk Gustav Stålhammar Charlotta All-Eriksson Henrik Ring Finn Hallböök MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma Oncogenesis |
| title | MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma |
| title_full | MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma |
| title_fullStr | MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma |
| title_full_unstemmed | MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma |
| title_short | MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma |
| title_sort | mycn induces cell specific tumorigenic growth in rb1 proficient human retinal organoid and chicken retina models of retinoblastoma |
| url | https://doi.org/10.1038/s41389-022-00409-3 |
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