Analysis of the RNA-interactome governing oncogenesis of osteosarcoma

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Osteosarcoma is the most common primary malignant bone tumor in children, adolescents and young adults. Long term survival has improved from about 10% with surgical resection of the tumor alone to about 60%-75% with the introduction of chemotherapy in the 1970ies. However, since this progress has been achieved approx. 40 years ago, there has been almost no further improvement of survival rates. One of the challenges of developing new treatment options and of gaining new insights into the biology of osteosarcoma has been the lack of preclinical models reflecting key characteristics of this disease. In our previous work we have thus established a series of preclinical orthotopic mouse and cell culture models faithfully reflecting important features of the primary tumors. These models thus represent valuable tools to analyze mechanisms of the oncogenesis of osteosarcoma and to preclinically develop novel treatment strategies. Despite extensive genomic, epigenomic and transcriptomic analyses there is no unifying genetic mechanism explaining the development of osteosarcomas. This project is based on the hypothesis that RNA:protein interactions play key roles in the oncogenesis of osteosarcoma. We have now leveraged the invention and the refinement of the methodology for global RNA-interactome analysis in living cells by of one of the applicants and the development of patient-derived preclinical models in the laboratory of the other. We thus aim at gaining insight into a previously unrecognized level of gene regulation in the oncogenesis of osteosarcoma. The overall objectives of this project are (1) to comprehensively decipher the differences of the RNA-interactomes between normal osteoblasts and mesenchymal cells vs. patient-derived osteosarcoma cells (2) to study the dynamics of RNA-interactomes of osteosarcoma cells during the evolution from first diagnosis to relapse in the same patient, (3) to functionally validate top-scoring candidates resulting from the unbiased global analysis, and (4) to identify and test potential therapeutic targets in osteosarcoma cells which are based on their specificity in osteosarcoma cells, clinical data, dynamics in cancer evolution and on post-translational modifications of the RNA-binding proteins.