Inferring Bladder Cancer Evolution from Mucosal field Effects by Whole-Organ Spatial Mutational, Proteomic, and...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Bladder cancer development involves complex molecular alterations originating in the seemingly normal bladder mucosa.
• Understanding the spatial and temporal evolution of these changes is crucial for early detection and intervention.

Approach:

• Utilized multi-platform spatial mapping (mutational, proteomic, metabolomic) on a whole-organ scale.
• Analyzed microscopically normal bladder mucosa adjacent to cancerous tissues.
• Modeled mutation dynamics to delineate carcinogenesis phases and timelines.

Key Points:

• Identified widespread proteomic and metabolomic dysregulation in normal mucosa, preceding cancer.
• Discovered defects in protein homeostasis and altered urothelial differentiation impacting lipid and energy metabolism.
• Characterized three mutation types (α, β, γ) with distinct spatial distributions and roles in cancer progression.
• Modeled a 30-year carcinogenesis process with dormant (α mutations) and progressive (β and γ mutations) phases.

Conclusions:

• Bladder cancer initiation is a lengthy process originating from widespread mucosal field defects.
• Whole-organ mapping reveals critical insights into the molecular evolution and multi-stage development of bladder cancer.
• The study highlights the importance of the mucosal microenvironment in bladder carcinogenesis.