Grant: Project Grant

Genes can produce multiple distinct products through a process called "RNA splicing". The normal splicing pattern of genes is often disrupted in cancer, and many of the molecules that result from this abnormal splicing have been functionally implicated in cancer malignancy. However, the underlying cellular mechanisms that govern RNA splicing and the extent to which they play a role in cancer progression remain largely unknown. To address this challenge, we have developed new computational frameworks that, in combination with large-scale genomics data, can identify novel factors that are involved in RNA splicing. Using this approach, we have discovered and partly characterized a previously unknown RNA element that drives abnormal splicing in highly metastatic breast cancer. We have also identified the associated protein that interacts with this novel RNA element - through this interaction, this protein can change the splicing of gene products and lead to metastasis. Our studies also indicate that the role of this protein is not limited to breast cancer, and it may in fact be involved in multiple other cancer types. In this project, we will build on these recent developments to perform a detailed dissection of RNA splicing programs across different cancers, identify the genes that are modified as a result of abnormal splicing, cellular and molecular deficits that drive abnormal splicing, and their contribution to cancer development, progression, and metastasis. This study will enable us to obtain a better understanding of how the cellular behaviour and function changes in cancer and how tumour cells become metastatic, and may lead to new avenues for development of therapeutic strategies.