A Spatial Atlas of Muscle-Invasive Bladder Cancer Reveals Lineage-Specific Vulnerabilities and Immune Architecture

Area of Science:

• Oncology
• Genomics
• Spatial Biology

Background:

• Muscle-invasive bladder cancer (MIBC) exhibits clinical heterogeneity not fully captured by current molecular subtypes.
• The spatial organization of tumor states and microenvironment is crucial for understanding MIBC progression and treatment response.

Purpose of the Study:

• To construct a spatial atlas of MIBC by integrating multi-omic data.
• To identify spatial axes and their association with genomic instability, transcriptional plasticity, and immune infiltration.
• To define a spatial framework for understanding therapeutic vulnerabilities in MIBC.

Main Methods:

• Integration of spatial transcriptomics from 22 MIBC tumors with matched bulk RNA and whole-exome sequencing data.
• Construction of a spatial atlas to analyze tumor heterogeneity and microenvironment.
• Pan-cohort analyses across over 3,000 tumors to validate findings.

Main Results:

• Identification of a continuous, spatially organized luminal-to-basal axis within MIBC tumors.
• Luminal states enriched for FGFR3/NECTIN4; basal-like states at invasive margins associated with EGFR signaling, EMT, and immune infiltration.
• Spatial differences in tertiary lymphoid structures and conserved FGFR3-EGFR lineage exclusivity observed.

Conclusions:

• The spatial organization of MIBC is critical for defining tumor states, immune architecture, and therapeutic vulnerabilities.
• The identified luminal-basal axis provides a framework for understanding chemotherapy sensitivity and potential therapeutic targets.
• Spatial multi-omic analysis advances our understanding of MIBC heterogeneity and treatment resistance.