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Peer-reviewedCC BYCell death & disease

Single-cell profiling uncovers a rare mesenchymal-like urothelial state associated with sarcomatoid bladder cancer.

  • Justine J Jacobi1,2
  • Dongbo Xu1
  • Kyle Wieczorek1
  • Li Wang1
  • Yali Zhang2
  • Jianmin Wang2
  • Prashant K Singh3
  • Bo Xu4
  • Han Yu2
  • Ahmed A Hussein1
  • David W Goodrich1,5
  • Qiang Li6,7
7 affiliations
  1. 1Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  2. 2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  3. 3Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  4. 4Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  5. 5Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  6. 6Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
  7. 7Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
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Abstract

The bladder urothelium is a stratified epithelium, composed of basal, intermediate, and umbrella cells. While epithelial-mesenchymal transition is known to occur during bladder regeneration, carcinogenesis, and bladder cancer tumor progression, it remains unclear whether normal urothelial cells intrinsically possess a hybrid mesenchymal-like epithelial state. We analyzed scRNA-seq data of EPCAM+ urothelial cells from both mouse and human urothelium. Here, we identified and characterized a rare population of mesenchymal-like urothelial cells, termed M-cells, representing approximately 1-3% of urothelial cells. Vimentin-positive cells were evaluated by immunostaining to determine their distribution of M-cells in normal urothelial layers. M-cells are enriched within the basal layer but are present across all urothelial compartments. M-cells co-express epithelial markers with mesenchymal and stemness genes and engage stem cell-associated transcriptional regulators. Lineage tracing with the Upk2-Cre;mT/mG reporter mice confirmed their urothelial origin, excluding a fibroblast lineage. M-cells exhibit high transcriptional plasticity between basal cells and intermediate cells. In addition, we identified a 16-gene transcriptional signature uniquely expressed in M-cells but absent in fibroblasts. RNA deconvolution of MB49 tumors demonstrated strong enrichment of M-cell signature, suggesting that MB49 tumors are more likely to represent sarcomatoid urothelial carcinoma rather than fibroblast-derived sarcoma. The clinical relevance of the M-cell state was validated in primary human sarcomatoid bladder cancer tumors and their corresponding patient-derived xenografts. Together, these findings establish rare and transcriptionally unique M-cells within the normal urothelium as a novel highly plastic population with clinical implications for both mouse and human sarcomatoid urothelial carcinoma.

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Cite

BibTeXRIS
BibTeX
@article{jacobi2026singlecell,
  title = {{Single-cell profiling uncovers a rare mesenchymal-like urothelial state associated with sarcomatoid bladder cancer.}},
  author = {Justine J Jacobi and Dongbo Xu and Kyle Wieczorek and Li Wang and Yali Zhang and Jianmin Wang and Prashant K Singh and Bo Xu and Han Yu and Ahmed A Hussein and David W Goodrich and Qiang Li},
  journal = {Cell death \& disease},
  year = {2026},
  month = aug,
  doi = {10.1038/s41419-026-09136-8},
  url = {https://europepmc.org/article/MED/42967922},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Single-cell profiling uncovers a rare mesenchymal-like urothelial state associated with sarcomatoid bladder cancer.
AU  - Justine J Jacobi
AU  - Dongbo Xu
AU  - Kyle Wieczorek
AU  - Li Wang
AU  - Yali Zhang
AU  - Jianmin Wang
AU  - Prashant K Singh
AU  - Bo Xu
AU  - Han Yu
AU  - Ahmed A Hussein
AU  - David W Goodrich
AU  - Qiang Li
PY  - 2026
DA  - 2026/08/04
JO  - Cell death & disease
DO  - 10.1038/s41419-026-09136-8
UR  - https://europepmc.org/article/MED/42967922
AB  - The bladder urothelium is a stratified epithelium, composed of basal, intermediate, and umbrella cells. While epithelial-mesenchymal transition is known to occur during bladder regeneration, carcinogenesis, and bladder cancer tumor progression, it remains unclear whether normal urothelial cells intrinsically possess a hybrid mesenchymal-like epithelial state. We analyzed scRNA-seq data of EPCAM+ urothelial cells from both mouse and human urothelium. Here, we identified and characterized a rare population of mesenchymal-like urothelial cells, termed M-cells, representing approximately 1-3% of urothelial cells. Vimentin-positive cells were evaluated by immunostaining to determine their distribution of M-cells in normal urothelial layers. M-cells are enriched within the basal layer but are present across all urothelial compartments. M-cells co-express epithelial markers with mesenchymal and stemness genes and engage stem cell-associated transcriptional regulators. Lineage tracing with the Upk2-Cre;mT/mG reporter mice confirmed their urothelial origin, excluding a fibroblast lineage. M-cells exhibit high transcriptional plasticity between basal cells and intermediate cells. In addition, we identified a 16-gene transcriptional signature uniquely expressed in M-cells but absent in fibroblasts. RNA deconvolution of MB49 tumors demonstrated strong enrichment of M-cell signature, suggesting that MB49 tumors are more likely to represent sarcomatoid urothelial carcinoma rather than fibroblast-derived sarcoma. The clinical relevance of the M-cell state was validated in primary human sarcomatoid bladder cancer tumors and their corresponding patient-derived xenografts. Together, these findings establish rare and transcriptionally unique M-cells within the normal urothelium as a novel highly plastic population with clinical implications for both mouse and human sarcomatoid urothelial carcinoma.
SN  - 2041-4889
ER  -