Project 2: Splicing Dysregulation in Cancer

PROJECT 2 – RNA-SPLICING DYSREGULATION IN CANCER PROJECT SUMMARY The overarching goal of Project 2 is to understand the various roles of alternative splicing in pancreatic and breast cancer, and to exploit cancer-specific features of this process to develop targeted-therapeutic approaches. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the isoforms that are inappropriately expressed contribute to tumorigenesis or altered cell metabolism. The mechanisms and pathways through which the splicing-factor oncoprotein SRSF1 accelerates transformation of pancreas ductal cells, and its reciprocal regulation with mutant KRAS, will be investigated. The spliceosomal core component BCAS2 will be studied to understand the impact of its elevated expression on alternative splicing and tumorigenesis in pancreatic and breast cancers. Organoid models, as well as orthotopic and genetic mouse models, will be used to study tumorigenesis promoted by these splicing factors when their expression is elevated in pancreatic or breast cancer, with an emphasis on basal-like subtypes. High-throughput RNA-sequencing and computational analyses will be employed to identify and compare the affected splicing targets of SRSF1 and BCAS2 in these different cancer contexts, and selected target isoforms will be characterized and manipulated to evaluate their contributions to tumorigenesis and potential as therapeutic targets. One key event, alternative splicing of pyruvate kinase M pre-mRNA, which controls the distinctive glycolytic metabolism of cancer cells, will be thoroughly investigated as a potential therapeutic target, by specifically manipulating this process in vitro and in vivo, using antisense technology and organoid and mouse models of pancreatic and breast cancer.