Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Abstract Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47031-y |
| _version_ | 1797219759845015552 |
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| author | Yang Zhou Partho Sarothi Ray Jianguo Zhu Frank Stein Mandy Rettel Thileepan Sekaran Sudeep Sahadevan Joel I. Perez-Perri Eva K. Roth Ola Myklebost Leonardo A. Meza-Zepeda Andreas von Deimling Chuli Fu Annika N. Brosig Kjetil Boye Michaela Nathrath Claudia Blattmann Burkhard Lehner Matthias W. Hentze Andreas E. Kulozik |
| author_facet | Yang Zhou Partho Sarothi Ray Jianguo Zhu Frank Stein Mandy Rettel Thileepan Sekaran Sudeep Sahadevan Joel I. Perez-Perri Eva K. Roth Ola Myklebost Leonardo A. Meza-Zepeda Andreas von Deimling Chuli Fu Annika N. Brosig Kjetil Boye Michaela Nathrath Claudia Blattmann Burkhard Lehner Matthias W. Hentze Andreas E. Kulozik |
| author_sort | Yang Zhou |
| collection | DOAJ |
| description | Abstract Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma. |
| first_indexed | 2024-04-24T12:38:45Z |
| format | Article |
| id | doaj.art-c8a044416b63443ebe99465720d460f3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:38:45Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c8a044416b63443ebe99465720d460f32024-04-07T11:23:58ZengNature PortfolioNature Communications2041-17232024-04-0115112210.1038/s41467-024-47031-ySystematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcomaYang Zhou0Partho Sarothi Ray1Jianguo Zhu2Frank Stein3Mandy Rettel4Thileepan Sekaran5Sudeep Sahadevan6Joel I. Perez-Perri7Eva K. Roth8Ola Myklebost9Leonardo A. Meza-Zepeda10Andreas von Deimling11Chuli Fu12Annika N. Brosig13Kjetil Boye14Michaela Nathrath15Claudia Blattmann16Burkhard Lehner17Matthias W. Hentze18Andreas E. Kulozik19Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)European Molecular Biology Laboratory (EMBL)Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)Department of Clinical Science, University of BergenGenomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University HospitalDepartment of Neuropathology, Institute of Pathology, Heidelberg University HospitalDepartment of Pediatric Oncology, Hematology and Immunology, Heidelberg University HospitalMolecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)Department of Oncology, Oslo University HospitalDepartment of Pediatrics and Children’s Cancer Research Center, Technical University of Munich, School of MedicineDepartment of Pediatric Oncology, Hematology and Immunology, Olga HospitalDepartment of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University HospitalMolecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL)Abstract Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.https://doi.org/10.1038/s41467-024-47031-y |
| spellingShingle | Yang Zhou Partho Sarothi Ray Jianguo Zhu Frank Stein Mandy Rettel Thileepan Sekaran Sudeep Sahadevan Joel I. Perez-Perri Eva K. Roth Ola Myklebost Leonardo A. Meza-Zepeda Andreas von Deimling Chuli Fu Annika N. Brosig Kjetil Boye Michaela Nathrath Claudia Blattmann Burkhard Lehner Matthias W. Hentze Andreas E. Kulozik Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma Nature Communications |
| title | Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| title_full | Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| title_fullStr | Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| title_full_unstemmed | Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| title_short | Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| title_sort | systematic analysis of rna binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma |
| url | https://doi.org/10.1038/s41467-024-47031-y |
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