TRIM29 is Critical for Bladder Cancer Progression and Modulates the Tumor-Immune Niche

Area of Science:

• Oncology
• Urology
• Molecular Biology

Background:

• Tripartite Motif-Containing Protein 29 (TRIM29), also known as ATDC, is upregulated in muscle-invasive bladder cancer (MIBC).
• TRIM29 is enriched in basal bladder cancer subtypes and promotes cancer cell migration and invasion.
• Basal-stem progenitor cells (K5+/K14+) are implicated as the cell of origin for MIBC.

Purpose of the Study:

• To determine if Trim29 expression in basal urothelial cells is required for MIBC development.
• To investigate the role of Trim29 in the inflammatory response and tumor microenvironment of bladder cancer.
• To elucidate the mechanisms by which TRIM29 contributes to bladder tumor formation and progression.

Main Methods:

• Utilized a genetically engineered mouse model (GEMM) with Trim29 knockout (KO) in K5+ basal urothelial cells.
• Exposed GEMM to a bladder-specific chemical carcinogen to induce MIBC.
• Analyzed urothelial TRIM29 expression under inflammatory and genotoxic stress in mice and humans.
• Assessed immune cell recruitment and inflammatory signaling pathways (e.g., STING) in Trim29 KO bladders.

Main Results:

• Trim29 expression in K5+ basal cells is critical for bladder tumor formation and invasive progression.
• Urothelial Trim29 KO in GEMM blocked MIBC development induced by chemical carcinogen.
• TRIM29 knockout enriched immune cell recruitment to the bladder and upregulated STING and inflammatory signaling.
• Urothelial TRIM29 expression is enhanced during inflammation in humans and under stress in mice.

Conclusions:

• TRIM29 plays a critical role in the immunomodulation of the bladder tumor microenvironment (TME).
• TRIM29 acts in concert with pro-migratory basal gene programs to expedite MIBC development.
• Targeting TRIM29 may offer a therapeutic strategy for bladder cancer by modulating the immune response and inhibiting tumor progression.