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The urothelial gene regulatory network: understanding biology to improve bladder cancer management

Oncogene volume 43, pages 1–21 (2024)Cite this article

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Abstract

The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as “luminal-enriched”, “basal-enriched” or “common” according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.

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Fig. 1: The urothelium: morphological and molecular stratification during differentiation.
Fig. 2: Established and novel candidate TF involved in urothelial differentiation and BLCA.
Fig. 3: An updated morphogenetic model of BLCA progression.
Fig. 4: Building a BLCA TF gene regulatory network.
Fig. 5: The single-cell transcriptomic landscape of urothelial BLCA.

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Acknowledgements

We thank David McConkey and Andrew Mason for critical review of a previous version of the manuscript, Jaime Martínez de Villarreal and other members of the Epithelial Carcinogenesis Group for valuable contributions.

Funding

This work was supported, in part, by a grant from Fundación Científica de la Asociación Española Contra el Cáncer to FXR and EL (PRYGN223005REAL). The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DR20/11790014. SC was supported by Fellowship PRE2018-085808 from Agencia Estatal de Investigación, co-financed by Fondo Social Europeo. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510.

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Authors and Affiliations

  1. Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Maria Ramal, Sonia Corral, Mark Kalisz, Eleonora Lapi & Francisco X. Real

  2. CIBERONC, Madrid, Spain

    Mark Kalisz, Eleonora Lapi & Francisco X. Real

  3. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Francisco X. Real

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  1. Maria Ramal
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All authors reviewed and summarized literature on the topic. MR also performed new bioinformatics analyses included in the manuscript. SC took the main responsibility for the illustrations.

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Correspondence to Francisco X. Real.

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Ramal, M., Corral, S., Kalisz, M. et al. The urothelial gene regulatory network: understanding biology to improve bladder cancer management. Oncogene 43, 1–21 (2024). https://doi.org/10.1038/s41388-023-02876-3

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