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

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 Deimling, Chuli Fu, Annika N. Brosig, Kjetil Boye, Michaela Nathrath, Claudia Blattmann, Burkhard Lehner, Matthias W. Hentze () and Andreas E. Kulozik ()
Additional contact information
Yang Zhou: Heidelberg University and European Molecular Biology Laboratory (EMBL)
Partho Sarothi Ray: Heidelberg University and European Molecular Biology Laboratory (EMBL)
Jianguo Zhu: European Molecular Biology Laboratory (EMBL)
Frank Stein: European Molecular Biology Laboratory (EMBL)
Mandy Rettel: European Molecular Biology Laboratory (EMBL)
Thileepan Sekaran: European Molecular Biology Laboratory (EMBL)
Sudeep Sahadevan: European Molecular Biology Laboratory (EMBL)
Joel I. Perez-Perri: European Molecular Biology Laboratory (EMBL)
Eva K. Roth: Heidelberg University and European Molecular Biology Laboratory (EMBL)
Ola Myklebost: University of Bergen
Leonardo A. Meza-Zepeda: Oslo University Hospital
Andreas Deimling: Heidelberg University Hospital
Chuli Fu: Heidelberg University Hospital
Annika N. Brosig: Heidelberg University and European Molecular Biology Laboratory (EMBL)
Kjetil Boye: Oslo University Hospital
Michaela Nathrath: School of Medicine
Claudia Blattmann: Olga Hospital
Burkhard Lehner: Heidelberg University Hospital
Matthias W. Hentze: Heidelberg University and European Molecular Biology Laboratory (EMBL)
Andreas E. Kulozik: Heidelberg University and European Molecular Biology Laboratory (EMBL)

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47031-y

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