Christian J. Braun, Ludwig-Maximilian Universität München (Prize winner 2017)

Targeting the coordinated splicing of regulatory detained introns as a novel therapy for metastasis

“Hematopoetic and lymphatic metastasis is responsible for more than 90% of deaths from cancer. We recently found that cells utilize the splicing rate of Detained Introns (DIs) to systematically and coordinately govern gene expression programs. ES cells utilize this mechanism to enter post-mitotic states, whereas tumor cells use the systematically deregulated splicing of DIs to strengthen their proliferative capacities. DI-based regulation of gene expression seems to be particularly important when cells rapidly rewire their gene expression landscape while adjusting to new functional requirements. During metastatic progression, tumor cells require such fundamental changes in gene expression to survive extreme environments that impose major obstacles such as lack of oxygen and nutrient supply. I will systematically elucidate the role of DI-governed gene expression programs during metastasis. To do so, I will first analyze differential levels of DI inclusion in matched metastatic and non-metastatic breast cancer cells by RNAseq. These data sets already exist, are well controlled, optimized for gene expression studies and publically available. I will then perform functional enrichment analyses to enrich for DI-regulated genes within metastasis-relevant gene sets such as cellular adhesion and invasion. In a second step, I will screen previously identified pharmacological inhibitors of DI biology for their impact on pro-metastatic DI-based gene expression programs.”