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Purpose <p>Muscle-invasive bladder cancer (MIBC) remains biologically heterogeneous, and clinicopathological variables do not fully capture epithelial-state remodeling linked to progression and treatment response. We developed an epithelial plasticity-related risk score (EPRS) and evaluated its prognostic, biological, and immunological relevance.</p> Methods <p>Using 368 primary TCGA-MIBC cases, we built a basal-luminal plasticity axis and integrated differential expression, correlation with the continuous plasticity index, and survival association to define 331 candidate genes. Consensus clustering, weighted gene co-expression network analysis, and 10 modeling strategies were used for subtype discovery and score development. EPRS was externally validated in GSE32894 and GSE13507 and further characterized by enrichment analysis, immune deconvolution, single-cell RNA sequencing, immunotherapy-related analyses, and nomogram construction.</p> Results <p>Two stable plasticity-associated subtypes showed distinct overall survival. WGCNA identified opposing lipid-metabolic and extracellular-matrix/injury-response programs. Among portable models, the Ridge-based EPRS showed the most stable cross-cohort performance and significantly stratified survival in TCGA-MIBC, GSE32894, GSE13507, and the pooled meta cohort. High-EPRS tumors were enriched for extracellular-matrix remodeling, inflammatory signaling, stromal expansion, and an immune-evasive microenvironment despite increased checkpoint-related expression. Single-cell analysis linked EPRS to a continuous malignant epithelial-state landscape. An EPRS-based nomogram improved individualized survival estimation.</p> Conclusions <p>EPRS captures a clinically relevant epithelial plasticity axis in MIBC and links poor outcome to stromal-immune remodeling and malignant epithelial-state organization.</p>

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A machine learning-guided epithelial plasticity score refines prognostication and immune-context stratification in muscle-invasive bladder cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月13日

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  • Difei Yu,
  • Yu Zhang,
  • Jiarun Tang,
  • Jing Qing,
  • Ke Hu,
  • Jiamo Zhang

摘要

Purpose

Muscle-invasive bladder cancer (MIBC) remains biologically heterogeneous, and clinicopathological variables do not fully capture epithelial-state remodeling linked to progression and treatment response. We developed an epithelial plasticity-related risk score (EPRS) and evaluated its prognostic, biological, and immunological relevance.

Methods

Using 368 primary TCGA-MIBC cases, we built a basal-luminal plasticity axis and integrated differential expression, correlation with the continuous plasticity index, and survival association to define 331 candidate genes. Consensus clustering, weighted gene co-expression network analysis, and 10 modeling strategies were used for subtype discovery and score development. EPRS was externally validated in GSE32894 and GSE13507 and further characterized by enrichment analysis, immune deconvolution, single-cell RNA sequencing, immunotherapy-related analyses, and nomogram construction.

Results

Two stable plasticity-associated subtypes showed distinct overall survival. WGCNA identified opposing lipid-metabolic and extracellular-matrix/injury-response programs. Among portable models, the Ridge-based EPRS showed the most stable cross-cohort performance and significantly stratified survival in TCGA-MIBC, GSE32894, GSE13507, and the pooled meta cohort. High-EPRS tumors were enriched for extracellular-matrix remodeling, inflammatory signaling, stromal expansion, and an immune-evasive microenvironment despite increased checkpoint-related expression. Single-cell analysis linked EPRS to a continuous malignant epithelial-state landscape. An EPRS-based nomogram improved individualized survival estimation.

Conclusions

EPRS captures a clinically relevant epithelial plasticity axis in MIBC and links poor outcome to stromal-immune remodeling and malignant epithelial-state organization.