Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Urothelial cancer (UC) treatment is evolving towards precision oncology.
• Molecular subtypes are critical for targeted therapy in metastatic UC (mUC).
• The stability of UC subtypes during metastatic progression is currently unknown.

Purpose of the Study:

• To investigate whether molecular subtypes of urothelial carcinoma change during metastatic evolution.
• To compare the stability of protein-based versus transcriptome-based subtypes.
• To inform future subtype-stratified clinical trials for mUC.

Main Methods:

• Analysis of a UC progression cohort (N=154) with matched primary tumors and metastases.
• Immunohistochemistry and mRNA sequencing were used to assess tumor subtypes.
• Comparison of subtype concordance between primary and metastatic lesions.

Main Results:

• Protein-based tumor cell subtypes remained stable during metastatic progression (94% concordance).
• Transcriptome-based molecular subtypes showed higher heterogeneity (45% concordance), with switches between luminal and stroma-rich types.
• Stroma-rich tumors exhibited luminal differentiation, with gene expression influenced by stromal content.

Conclusions:

• Immunohistochemistry reliably defines stable urothelial carcinoma subtypes (luminal, basal, neuroendocrine) during metastasis.
• Transcriptome analysis reveals greater heterogeneity, potentially due to stromal influence.
• Findings support the use of stable protein-based subtypes for future mUC clinical trials.