Using a multi-omics workflow powered by deep proteomic analysis, researchers at Baylor College of Medicine have mapped the molecular architecture of chemoresistant muscle-invasive bladder cancer (MIBC) – highlighting overlooked protein isoforms and signaling pathways that could inform more personalized treatment strategies.
The team applied an integrative approach to 60 tumor samples from chemotherapy-treated MIBC patients, analyzing DNA sequences (genomics), gene activity (transcriptomics), protein expression (proteomics), and phosphorylation status (phosphoproteomics). Proteins were profiled using tandem mass tag (TMT)–based quantitative mass spectrometry with extensive peptide fractionation and phosphopeptide enrichment, enabling deep coverage across protein isoforms and signaling networks.
“By computationally analyzing the vast information generated by the multi-omics approach, we produced a molecular profile for each tumor sample and hoped to uncover patterns linked to resistance to chemotherapy,” said first author Yongchao Dou in a press release.
One key finding involved protein isoforms – closely related variants of the same protein that can have distinct biological functions. While gene-level analyses missed these differences, MS-based proteomics revealed that specific isoforms of ATAD1 and RAF family kinases were enriched in chemotherapy-responsive tumors. “These isoforms weren’t detectable by looking at genes or RNA alone, highlighting the importance of studying proteins directly,” added co-author Matthew Holt.
The analysis also uncovered resistance-associated signaling activity. Chemoresistant tumors showed higher activation of the Wnt and JAK/STAT pathways, marked by elevated GSK3B and phosphorylated STAT3, respectively – suggesting that targeted inhibition of these pathways may help overcome resistance.
To explore future therapeutic potential, the researchers examined the expression of known targets of antibody-drug conjugates (ADCs), such as PD-L1, TROP2, and NECTIN-4. Expression patterns varied across molecular subtypes, supporting the rationale for combining ADCs with chemotherapy or immunotherapy in a subtype-specific manner.
“This study identified specific proteins and pathways linked to treatment resistance, as well as potential new ways to treat resistant tumors,” commented senior author Seth Lerner. “This is important because it provides insights that can help expand the population that can be treated effectively and improve overall patient outcomes.”
The researchers plan to further validate their findings in larger cohorts and explore therapeutic interventions targeting the resistance-associated isoforms and pathways identified.
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