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Ribosome defects in cancer

Final Report Summary - RIBOCANCER (Ribosome defects in cancer)

Transformation of a healthy cell into a cancer cell is caused by accumulation of genetic defects in vital cellular functions such as cell cycle control, apoptosis and response to growth signals. In the context of T-cell leukemia, we found that 10% of children show acquired mutations in ribosomal proteins, linking for the first time an acquired defect in the ribosome to cancer (De Keersmaecker et al., Nature Genetics, 2013). In this project, screening of genetic data from multiple cancer types revealed that acquired defects in ribosomal proteins are not restricted to T-cell leukemia and that there are several cancer types in which 10-20% of samples show defective ribosomal proteins.
We also explored the molecular mechanisms by which ribosome defects promote cancer. For one of the highly recurrent ribosome mutations we identified in T-cell leukemia, our results indicate that cellular protein production and degradation is affected, with particular proteins with established (JAK-STAT and BCL2) and less established (PSPH) roles in cancer promotion being strongly upregulated. We also showed that ribosomal mutations promote acquisition of additional cancer promoting mutations in cells, and identified an additional mutation (NOTCH1) that often co-occurs with the studied ribosomal protein mutation. Our data suggest that extra mutations such as NOTCH1 are required to correct effects from the ribosome defect that are in the disadvantage of a cancer cell and that such mutations are thus needed for full transformation to cancer. Overall, our mechanistic studies identified several critical nodes in ribosome defective cancer cells for which clinically used drugs are available. Within the framework of this project, BCL2 inhibitor venetoclax showed a high efficacy in a pre-clinical mouse model.
Overall, this project thus delineated the spectrum of somatic ribosome mutations in cancer and delivered valuable novel insights in the mode of action that ribosome defects utilize to promote cancer.