FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation

Area of Science:

• Oncology
• Urothelial Carcinogenesis
• Molecular Pathology

Background:

• Muscle-invasive bladder cancer (MIBC) subtypes exhibit varying prognoses, with FGFR3 mutations often associated with better survival in luminal papillary tumors.
• The precise role of FGFR3 mutations in bladder cancer initiation and progression remains incompletely understood.
• Tobacco carcinogens like N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) are established inducers of bladder tumorigenesis.

Purpose of the Study:

• To investigate the functional impact of specific FGFR3 mutations (S249C and K644E) on OH-BBN-induced bladder tumor development.
• To elucidate the relationship between FGFR3 mutations, inflammatory responses, and tumor progression in a preclinical model.
• To determine if altered inflammatory signaling contributes to the oncogenic effects of FGFR3 mutations.

Main Methods:

• Generation of genetically engineered mouse models expressing activated FGFR3 S249C or K644E mutations in the urothelium.
• Induction of bladder tumors using the carcinogen OH-BBN.
• Assessment of tumor occurrence, progression, and associated inflammatory infiltrates (neutrophils, lymphocytes) at different time points.
• Experimental manipulation of neutrophil populations using anti-Ly6G antibody to assess their role in pathogenesis.

Main Results:

• FGFR3 S249C mutations significantly increased the occurrence and progression of OH-BBN-induced bladder tumors compared to wild-type controls.
• Early-stage tumors with S249C mutations exhibited suppressed acute inflammatory responses to OH-BBN.
• Later-stage S249C tumors showed increased inflammation, and neutrophil depletion in early phases exacerbated later-stage tumor pathogenesis.

Conclusions:

• FGFR3 mutations, specifically S249C, can promote bladder tumor development and progression.
• Suppression of acute inflammation during early tumorigenesis may be a key mechanism by which FGFR3 mutations enhance tumor development.
• Altered inflammatory dynamics, driven by FGFR3 mutations, play a critical role in bladder cancer pathogenesis, particularly at pre-neoplastic stages.