Researchers at The University of Texas MD Anderson Cancer Center have developed a spatial map of muscle-invasive bladder cancer, revealing how tumor cell states, immune environments and therapeutic vulnerabilities are organized within tumors, according to a study published in Cancer Discovery on June 18. The research provides a new framework for understanding why patients with bladder cancer may respond differently to treatment.
The study was led by Linghua Wang, M.D., Ph.D., professor of Genomic Medicine and executive director and head of the Center for Cellular Language Intelligence; Jianjun Gao, M.D., Ph.D., professor of Genitourinary Medical Oncology; along with co-first authors Kai Yu, Ph.D., postdoctoral fellow in the Wang laboratory, and Jianfeng Chen, M.D., Ph.D., instructor of Genitourinary Medical Oncology.
To investigate why current biomarkers do not fully explain differing patient responses to treatment in muscle-invasive bladder cancer—a clinically heterogeneous disease—the researchers integrated spatial transcriptomics from 22 pretreatment tumors with matched whole-exome sequencing and bulk RNA sequencing. They also used single-cell RNA sequencing and single-cell spatial transcriptomics from additional tumors to validate findings at higher resolution.
The resulting spatial map showed that cancer cells can gradually change from one cell type (luminal) to another (basal) along a continuous differentiation axis within individual tumors. Luminal-like tumor cells were more often located in tumor cores and enriched for FGFR3 and NECTIN4 markers. Basal-like tumor cells appeared near invasive margins where they exhibited higher EGFR signaling, epithelial-mesenchymal transition programs, chromosomal instability and immune infiltration—features associated with aggressiveness.
Gao said, "An important message from this work is that effective treatment may need to account for both luminal and basal components within the same tumor, as well as their spatial organization. Rather than treating bladder cancer as a single uniform disease state, spatial information may help guide rational combinations or sequencing of therapies that target distinct tumor regions and cell states."
The study identified lineage-specific treatment vulnerabilities: luminal regions showed high NECTIN4 expression supporting it as a therapeutic target; basal-like regions were linked to immune-rich microenvironments and greater chemotherapy sensitivity. Further preclinical testing indicated NECTIN4 overexpression increased sensitivity to enfortumab vedotin—a NECTIN4-targeted antibody-drug conjugate—and shifted cells toward a more luminal-like state. The researchers found FGFR3 marked luminal states while EGFR was enriched in basal-like or plastic states across more than 3,000 independent cases.
The findings support developing spatially informed biomarkers so clinicians can better match therapies to specific tumor regions or cell types. Future studies will aim to validate these results in larger clinical cohorts including post-treatment samples.
