Proteomic profiling identifies muscle-invasive bladder cancers with distinct biology and responses to platinum-based chemotherapy

A. Contreras-Sanz (), G. L. Negri, M. J. Reike, H. Z. Oo, J. M. Scurll, S. E. Spencer, K. Nielsen, K. Ikeda, G. Wang, C. L. Jackson, S. Gupta, M. E. Roberts, D. M. Berman, R. Seiler, G. B. Morin and P. C. Black ()
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A. Contreras-Sanz: University of British Columbia
G. L. Negri: University of British Columbia
M. J. Reike: University of British Columbia
H. Z. Oo: University of British Columbia
J. M. Scurll: University of British Columbia
S. E. Spencer: University of British Columbia
K. Nielsen: University of British Columbia
K. Ikeda: University of British Columbia
G. Wang: University of British Columbia
C. L. Jackson: Queen’s University
S. Gupta: The Cleveland Clinic
M. E. Roberts: University of British Columbia
D. M. Berman: Queen’s University
R. Seiler: University of British Columbia
G. B. Morin: University of British Columbia
P. C. Black: University of British Columbia

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Platinum-based neoadjuvant chemotherapy prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer despite modest survival benefit and significant associated toxicities. Here, we profile the global proteome of muscle-invasive bladder cancers pre- and post-neoadjuvant chemotherapy treatment using archival formalin-fixed paraffin-embedded tissue. We identify four pre-neoadjuvant chemotherapy proteomic clusters with distinct biology and response to therapy and integrate these with transcriptomic subtypes and immunohistochemistry. We observe proteomic plasticity post-neoadjuvant chemotherapy that is associated with increased extracellular matrix and reduced keratinisation compared to pre-neoadjuvant chemotherapy. Post-neoadjuvant chemotherapy clusters appear to be differentially enriched for druggable proteins. For example, MTOR and PARP are over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determine that high intra-tumoural proteome heterogeneity in pre-neoadjuvant chemotherapy tissue is associated with worse prognosis. Our work highlights aspects of muscle-invasive bladder cancer biology associated with clinical outcomes and suggests biomarkers and therapeutic targets based on proteomic clusters.

Date: 2025
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DOI: 10.1038/s41467-024-55665-1

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