Combinatorial genetic strategy accelerates the discovery of cancer genotype-phenotype associations [RNA-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: Bulk RNA-seq was performed on laser captured section of FFPF samples of bladder tumors with different histology generated by transducing the bladder urothelial cells with a pooled lentivirus containing candidate oncogenic events to profile the transcriptome of tumors with different phenotypes. Analysis was performed to compare transcriptome profile of the tumors from different histology group.