Summary The project has historically studied the action of tumor suppressor genes, and is based on the premise that tumor suppressors reveal key regulatory nodes in growth control processes and the strategies nature uses to combat cancer. Based on our observation that certain oncogenes promote apoptosis through p53, we initially explored the mechanisms by which p53 suppressed apoptosis and how disruption of p53 network components promoted tumorigenesis and impacted therapy response. Taking advantage of program collaborations, we later established how p53 loss sustains tumorigenesis and, by combining oncogenomics, functional genomics, and in vivo genetic screens, established the functional relevance of many cancer drivers. Over the last funding cycle, we expanded our efforts towards understanding how tumor suppressor loss is required for tumor maintenance, showing that re-establishing tumor suppressor networks can have profound and distinct anti- proliferative effects, even in advanced cancers. This evolution spawned our current interest in “tumor maintenance genes” – genes needed to sustain cancer progression – and stimulated the development of new mouse models that enable suppression and/or reactivation of gene function at different stages of disease. Moving forward, the project will focus on the identification and characterization of tumor suppressor and tumor maintenance genes in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) – two primary liver cancers for which genomic studies have identified few “druggable” cancer drivers, and for which no effective therapies exist. As such, we now propose to characterize how mutations in certain chromatin-modifying genes – which are common in human tumors but are poorly understood - drive tumor initiation and maintenance, and to implement new genetic and genomic tools to identify and validate therapeutic targets for primary liver cancers driven by these altered gene products. Our approach combines mouse models, genetic tools, and cancer genomics in a coordinated manner that enables the comprehensive interrogation of tumor suppressor and tumor maintenance network, and benefits from multiple interactions with other projects and cores. The project will produce a more complete understanding of how primary liver cancers are initiated and maintained while simultaneously validating new therapeutic targets for these diseases. As such, our project addresses an urgent and unmet clinical need.