(UroToday.com) Urothelial carcinoma occurs throughout the urinary tract. The predominance of urothelial carcinoma of the bladder (UCB) has limited study of upper tract urothelial carcinoma (UTUC). UTUC is a rare disease with worse outcomes than UCB despite their high commonality in risk factors, mutational profiles and molecular subtypes. Whilst histologically-normal urothelium from bladder and upper tract tissues appears highly convergent, they investigated the underlying genomic architecture and transcriptomic networks to identify features that explain divergent UTUC/UCB progression.
Human bladder and ureteric urothelium were isolated from surgical samples and taken for scRNAseq or bulk DNA/RNA, or expanded and re-differentiated to a biomimetic tissue. This enabled comparison of chromatin state (ATACseq) and transcriptomic profile (bulk and single-cell RNAseq) in adult tissue, and assessment of differentiation regulatory networks. Tissue-specific profiles were used to interrogate publicly available UCB and UTUC datasets.
Reflective of their convergent phenotype, differentiated and native bladder and ureteric urothelium exhibited highly similar transcriptomic and chromatin profiles. Bladder urothelium typically appeared “more” differentiated, with higher expression of luminal markers, and better resolved superficial cells by scRNAseq. Archetypal differentiation regulating transcription factors were not different between tissues. However, germ layer differences resulted in a homeobox axis: posterior in bladder, anterior in ureter. Tumours typically retained this axis, though 10% of TCGA muscle-invasive UCBs were consistent with a ureteric origin, highlighting UTUC intraluminal seeding of cancers in the bladder. Differential homeobox usage was responsible for divergent top-level transcriptomic networks in ureter and bladder urothelium. Ureteric urothelium was predominantly driven by retinoid signalling, and bladder by WNT signaling, highlighting novel therapeutic routes.
In summary, despite different embryonic origins, bladder and ureter urothelium is highly similar, now confirmed down to molecular and single-cell resolution. However, the two tissues are reliant on different top-level transcriptomic regulation and this provides opportunity for more personalised treatment of UTUC.
Presented by: Andrew Mason, The University of York, York, UK
Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain