Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations

Available genetically-defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Herein, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes. ### Competing Interest Statement J.K.L. served on the Speakers Bureau for Mission Bio, Inc. B.M.F.: Consulting or Advisory Role: QED Therapeutics, Boston Gene, Astrin Biosciences Merck, Immunomedics/Gilead, Guardant, Janssen. Patent Royalties: Immunomedics/Gilead. Research support: Eli Lilly.