Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations [scDNA-Seq]
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. Overall design: scDNA sequencing was performed on the bladder/prostate tumors generated by transducing the bladder urothelial cells with a pooled lentivirus containing candidate oncogenic events, in order to deconvolute the clonality and heterogenity formed in the generated tumors. Different cell populations were identified in each tumor samples with enriched candidate factors in each population.