Progression-associated molecular changes in basal/squamous and sarcomatoid bladder carcinogenesis.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Basal/squamous (Ba/Sq) bladder cancer (BLCA) is aggressive, often diagnosed at the muscle-invasive stage (MIBC).
• Progression to sarcomatoid variant and understanding molecular changes from non-muscle-invasive BLCA (NMIBC) to MIBC are challenging.
• The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model mimics Ba/Sq MIBC and sarcomatoid variant development.

Purpose of the Study:

• To longitudinally investigate molecular alterations during Ba/Sq BLCA progression and sarcomatoid dedifferentiation using a mouse model.
• To identify molecular drivers and potential biomarkers for bladder cancer progression.
• To explore signaling pathway shifts and their role in epithelial-mesenchymal transition (EMT).

Main Methods:

• Longitudinal study of the BBN mouse model of Ba/Sq MIBC.
• Immunohistochemistry (IHC), microdissection, and RNA sequencing (RNA-seq) at various progression stages.
• Pathway analysis of gene expression and correlation with human NMIBC data.

Main Results:

• A shift towards the Ba/Sq phenotype begins in early progression stages.
• Loss of Shh signaling and a metabolic shift from fatty acid metabolism to glycolysis were observed.
• An early-upregulated gene cluster identified NMIBC patients at risk of progression.
• Sarcomatoid tumors showed Ba/Sq phenotype, EMT features, and an EGFR/FGFR1 signaling switch.
• BLCA cell lines with high EMT were sensitive to FGFR1 knockout and resistant to EGFR knockout.

Conclusions:

• Early molecular changes in Ba/Sq BLCA progression include Shh signaling loss and metabolic reprogramming.
• Specific gene expression patterns can predict NMIBC progression risk.
• EGFR/FGFR1 signaling dynamics are linked to sarcomatoid dedifferentiation and EMT in BLCA.
• Findings offer insights into Ba/Sq BLCA biology and sarcomatoid variant development with potential clinical relevance.