Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Charles C. Guo, Tadeusz Majewski, Li Zhang, Hui Yao, Jolanta Bondaruk, Yan Wang, Shizhen Zhang, Ziqiao Wang, June Goo Lee, Sangkyou Lee, David Cogdell, Miao Zhang, Peng Wei, H. Barton Grossman, Ashish Kamat, Jonathan James Duplisea, James Edward Ferguson, He Huang, Vipulkumar Dadhania, Jianjun GaoColin Dinney, John N. Weinstein, Keith Baggerly, David McConkey, Bogdan Czerniak

Research output: Contribution to journalArticle

Abstract

Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer. Guo et al. report that sarcomatoid carcinoma of the bladder evolves by the progression of the basal subtype of conventional urothelial carcinoma with the enrichment of mutagenesis signature 1 and mutations of TP53, RB1, and PIK3CA. It is driven by the dysregulation of the EMT network and shows increased immune infiltrate with overexpression of PD-L1.

Original languageEnglish (US)
Pages (from-to)1781-1793.e4
JournalCell Reports
Volume27
Issue number6
DOIs
StatePublished - May 7 2019

Keywords

  • basal subtype
  • bladder cancer
  • chromatin remodeling
  • epithelial-mesenchymal transformation
  • genomic expression
  • immune phenotype
  • microRNA expression
  • molecular classification
  • sarcomatoid carcinoma
  • urothelial carcinoma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Guo, C. C., Majewski, T., Zhang, L., Yao, H., Bondaruk, J., Wang, Y., Zhang, S., Wang, Z., Lee, J. G., Lee, S., Cogdell, D., Zhang, M., Wei, P., Grossman, H. B., Kamat, A., Duplisea, J. J., Ferguson, J. E., Huang, H., Dadhania, V., ... Czerniak, B. (2019). Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer. Cell Reports, 27(6), 1781-1793.e4. https://doi.org/10.1016/j.celrep.2019.04.048