Winners 2017

Christian J. Braun LMU München

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."

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Manuel Valiente CNIO Madrid

Altered brain vessels as a novel target in brain metastasis

"Brain metastasis is an unmet need in high demand of novel and effective therapies. We propose to develop an innovative approach aiming to evaluate the possibility of targeting pro-metastatic components of the microenvironment induced by cancer cells. Speciifically we propose to focus our efforts on brain metastasis associated vessels. We previously defined the critical contribution of the interaction between cancer cells and vessels for the progression of metastasis in the brain. We now want to discover molecular alterations induced by the presence of brain metastatic cells on endothelial cells. We will consider the process of vascular co-option (occurring early during brain colonization) as well as angiogenesis (occurring at more advanced stages of brain metastasis) as the targets of our research. Describing these altered states of brain vessels compared to normal vessels will be critical to initiate an ambitious project aimed to define molecular alterations in endothelial cells correlating with altered permeability to drugs, novel therapeutic targets to impair the progression of brain metastasis as well as innovative biomarkers. In this proposal we describe a research plan to perform a comprehensive molecular characterization of brain metastasis associated vessels, which will be the central pillar for subsequent mechanistic and funktional studies. "