Contribution of heterozygous loss of ribosomal protein L5 to glioblastoma pathogenesis

The association between ribosome defects and cancer became clear with the recent discovery of somatic mutations in ribosomal protein genes in multiple human cancers. Together with the host Laboratory, mutation, copy number and methylation data from all available cancer types in the Cancer Genome Atlas (TCGA) were integrated. This revealed that the frequency of defects in ribosomal protein RPL5 are still underestimated and that several cancer types show heterozygous inactivation of RPL5 by mutations, deletions and hypermethylation in up to 30% of samples, suggesting a common tumor suppressor function for RPL5 in cancer. Moreover, RPL5 inactivation is associated with poor clinical outcomes, especially in glioblastoma. Although some physiological roles for RPL5 are known, the pathologic consequences of heterozygous loss of RPL5 are currently unclear. In this project, we will establish glioblastoma cell lines and mouse tumors modelling heterozygous RPL5 loss. We will then exploit these models to investigate the tumor suppressor role of RPL5 in the context of glioblastoma. This will allow us to identify vulnerable nodes in the network downstream of heterozygous loss of RPL5 that we can validate as therapeutic targets in GBM.