Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations [scDNA-seq_MOI]

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 models of bladder and prostate cancer. 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. scDNA sequencing was performed on the prostate organoid cells transduced with different MOI of the pooled lentivirus containing candidate oncogenic events. Different cell population with different virus copy number were retrieved to compare the transduction efficiency in each MOI group.