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<p>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 <i>Upk2-Cre</i>;<i>mT/mG</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Justine J. Jacobi,
  • Dongbo Xu,
  • Kyle Wieczorek,
  • Li Wang,
  • Yali Zhang,
  • Jianmin Wang,
  • Prashant K. Singh,
  • Bo Xu,
  • Han Yu,
  • Ahmed A. Hussein,
  • David W. Goodrich,
  • Qiang Li

摘要

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.