The use of model organisms and patient-derived xenografts (PDX) are valuable tools in advanced preclinical oncology research for disease progression and drug development. Bladder cancer is caused by upwards of 5 mutations or more in the same tumor. Studying diverse higher-order genetic interactions that drive bladder cancer is difficult with current models of tumorigenesis and limited by bulk sequencing, which fails to directly discern clonality and resolve mutational co-occurrence patterns. Dr. John Lee, of Fred Hutchinson Cancer Center, sought to better understand which combinations of mutations were critical by leveraging a mouse model, organoids, and gene-editing approaches. Using single-cell DNA sequencing, a system was developed for investigating the functional impact of higher-order genetic interactions in cancer.