A multi-modal spatial genomics study of 22 untreated bladder tumours has challenged the binary luminal-basal classification model, identifying distinct tumour regions with differing therapeutic vulnerabilities and immune profiles that could inform more personalised treatment strategies.
Researchers at The University of Texas MD Anderson Cancer Center (UTMD) have created a detailed spatial map of muscle-invasive bladder cancer, giving scientists a better understanding of how tumour cells and their surrounding immune environments are organised. The findings suggest that comprehending the physical layout of tumours could help clinicians tailor treatments more effectively in the future.
Mapping the tumour landscape
Current approaches often classify muscle-invasive bladder cancer into either luminal or basal molecular subtypes. However, the new research suggests this simplified classification does not reflect the complexity found within individual tumours.
By combining spatial transcriptomics with whole-exome sequencing, bulk RNA sequencing and single-cell analysis, the research team examined 22 untreated bladder tumours before validating their findings using additional patient samples.
Their analysis showed that luminal and basal-like cancer cells can exist side by side within the same tumour, forming highly organised spatial patterns rather than representing separate tumour types.
“Traditional molecular subtyping often classifies bladder cancers as either luminal or basal but our spatial analyses show that this binary view is incomplete,” said research leader, Dr Linghua Wang. “Within a single patient’s tumour, luminal and basal-like programs can coexist in highly organised spatial patterns and those patterns are closely tied to immune activity, lineage-specific treatment vulnerabilities and how different tumour regions may respond to treatment.”
Studies such as this highlight how understanding disease often requires more than studying cells in isolation. Our latest report explores how spatial biology is revealing aspects of disease biology that cannot be captured through individual cells alone, and what that could mean for biomarker discovery, immunotherapy and drug development.
Distinct regions with different vulnerabilities
The researchers found that luminal-like tumour cells were typically concentrated in the tumour core and frequently expressed the therapeutic markers FGFR3 and NECTIN4. In contrast, basal-like cells were more commonly located around the invasive edges of tumours where they displayed stronger EGFR signalling, greater chromosomal instability and increased immune cell infiltration, all characteristics linked with more aggressive disease.
The findings indicate that different parts of the same tumour may respond differently to available therapies, potentially leading to more targeted treatment strategies.
Further laboratory testing supported this idea. Tumour cells with higher NECTIN4 expression were more sensitive to the antibody-drug conjugate enfortumab vedotin, while basal-like regions appeared more responsive to chemotherapy because of their immune-rich environment.
Towards more personalised treatment
The study also identified FGFR3 and EGFR as markers representing opposite ends of the luminal-basal spectrum, offering another way to assess tumour behaviour. These patterns were subsequently validated across more than 3,000 bladder tumours from independent patient cohorts.
“An important message from this work is that effective treatment may need to account for both luminal and basal components within the same tumour, as well as their spatial organisation,” said Dr Jianjun Gao, Professor of Genitourinary Medical Oncology at UTMD. “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 tumour regions and cell states.”
The researchers believe future spatially informed biomarkers could help clinicians identify which treatments are most likely to benefit specific tumour regions, potentially improving outcomes for patients with bladder cancer. Larger clinical studies will now be needed to confirm the findings and determine how tumour architecture changes following treatment.
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