Despite significant efforts, genetic alterations that specifically promote metastatic phenotypes have not been identified. However, cancers with high propensity to metastasize have distinct transcriptional profiles. This suggests that metastatic programming in primary tumours is largely caused by aberrations in transcriptional control. Nevertheless, how metastatic transcriptional programs arise has remained elusive. We will use experimental metastasis models to identify critical transcriptional control mechanisms of metastatic progression. First, we will use established clones of varying metastatic potential to perform chromatin and transcriptional profiling (ATAC-seq, RNA-seq and ChIP-seq). Using computational methods with clinical validation, we will identify candidate gene regulatory regions and their regulators underlying metastasis. We will then use experimental genetics (gene and gene regulatory element loss-of-function and gain-of-function) to identify functional drivers of metastatic transcriptional programs.