Language

English

Publication Date

8-19-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102255

PMID

40749681

PMCID

PMC12432383

PubMedCentral® Posted Date

7-31-2025

PubMedCentral® Full Text Version

Post-print

Abstract

To explore potential chemoresistance mechanisms and identify therapeutic opportunities in muscle-invasive bladder cancer (MIBC), we conduct comprehensive proteogenomic characterization of 46 pre- and 14 post-treatment MIBC tumors incorporating genomics, transcriptomics, proteomics, and phosphoproteomics. Multi-omics clustering not only recapitulated established molecular subtypes but also revealed subtypes associated with chemotherapy sensitivity. Protein isoform level analysis identifies protein abundance of a short isoform of ATAD1 and RAF family proteins as biomarkers of chemosensitivity. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive benefit of combination therapy targeting these proteins. Overall, this study serves as a valuable resource for researchers and clinicians aiming to better understand and treat chemoresistant MIBC.

Keywords

Humans, Urinary Bladder Neoplasms, Drug Resistance, Neoplasm, Biomarkers, Tumor, Proteogenomics, Male, Female, ATPases Associated with Diverse Cellular Activities, Neoplasm Invasiveness, Aged, Middle Aged, Signal Transduction, Proteomics, Cell Adhesion Molecules

Published Open-Access

yes

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