Clonal evolution and stromal crosstalk drive an invasive epithelial program in bladder cancer

Area of Science:

• Oncology
• Genomics
• Cell Biology

Background:

• Bladder cancer progression and metastasis are influenced by epithelial cell diversity and tumor microenvironment interactions.
• Understanding specific epithelial subpopulations is crucial for elucidating cancer advancement.

Purpose of the Study:

• To identify and characterize epithelial cell subpopulations associated with bladder cancer progression and metastasis.
• To investigate the genomic and microenvironmental factors contributing to aggressive tumor phenotypes.

Main Methods:

• Single-cell transcriptomic profiling of bladder cancer tissues.
• Copy Number Variation (CNV) analysis.
• Cell-cell communication and transcription factor network inference.
• Immunohistochemical validation.

Main Results:

• A distinct epithelial subset, Meta-program 6 (MP6), was identified, enriched in metastatic samples.
• The MP6 gene signature strongly correlates with advanced tumor stage, lymph node metastasis, and lymphovascular invasion.
• MP6 cells exhibit genomic instability (e.g., chromosome 19 deletion) and active crosstalk with cancer-associated fibroblasts via WNT and BMP signaling.
• Key transcription factors like TFCP2 and ELF1 were implicated in aggressive phenotypes.

Conclusions:

• A clonally evolved epithelial subtype (MP6) is associated with lymphatic invasion in bladder cancer.
• Stromal-epithelial interactions and tumor cell plasticity driven by MP6 contribute to bladder cancer progression.
• MP6 represents a potential therapeutic target for managing aggressive bladder cancer.