Classification of bladder cancer cell lines according to regulon activity

Bladder cancer is one of the most frequent cancers and causes more than 150.000 deaths each year. During the last decade, several studies provided important aspects about genomic characterization, consensus subgroup definition, and transcriptional regulation of bladder cancer. Still, much more research needs to be done to characterize molecular signatures of this cancer in depth. At this point, the use of bladder cancer cell lines is quite useful for the identification and test of new signatures. In this study, we classified the bladder cancer cell lines according to the activities of regulons implicated in the regulation of primary bladder tumors. Our regulon gene expression-based classification revealed three groups, neuronal-basal (NB), luminal-papillary (LP), and basal-squamous (BS). These regulon gene expression-based classifications showed a quite good concordance with the consensus subgroups assigned by the primary bladder cancer classifier. Importantly, we identified FGFR1 regulon to be involved in the characterization of the NB group, where neuroendocrine signature genes were significantly upregulated, and further β-catenin was shown to have significantly higher nuclear localization. LP groups were mainly driven by the regulons ERBB2, FOXA1, GATA3, and PPARG, and they showed upregulation of the genes involved in epithelial differentiation and urogenital development, while the activity of EGFR, FOXM1, STAT3, and HIF1A was implicated for the regulation of BS group. Collectively, our results and classifications may serve as an important guide for the selection and use of bladder cancer cell lines for experimental strategies, which aim to manipulate regulons critical for bladder cancer development.