Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma.

Autor: Zhou Y; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany., Ray PS; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany., Zhu J; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Stein F; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Rettel M; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Sekaran T; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Sahadevan S; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Perez-Perri JI; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Roth EK; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany., Myklebost O; Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Meza-Zepeda LA; Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., von Deimling A; Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany., Fu C; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany., Brosig AN; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Boye K; Department of Oncology, Oslo University Hospital, Oslo, Norway., Nathrath M; Department of Pediatrics and Children's Cancer Research Center, Technical University of Munich, School of Medicine, Munich, Germany.; Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany.; Department of Pediatric Oncology, Hematology and Immunology, Olga Hospital, Stuttgart, Germany., Blattmann C; Department of Pediatric Oncology, Hematology and Immunology, Olga Hospital, Stuttgart, Germany., Lehner B; Department of Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Heidelberg, Germany., Hentze MW; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. hentze@embl.org.; European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. hentze@embl.org., Kulozik AE; Molecular Medicine Partnership Unit (MMPU), Heidelberg University and European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.; Clinical Cooperation Unit Pediatric Leukemia, German Cancer Research Center (DKFZ) and Heidelberg University, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Apr 01; Vol. 15 (1), pp. 2810. Date of Electronic Publication: 2024 Apr 01.
DOI: 10.1038/s41467-024-47031-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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