Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors
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Updated: Jul 25, 2026
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Clarice S Groeneveld1, Virginia Sanchez-Quiles2, Florent Dufour3
1Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Centre de Recherche des Cordeliers, AP-HP, Université Paris Cité, Paris, France.
Background:
Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses.
Objective:
To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes.
Design, Setting, And Participants:
Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions.
Intervention:
Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial-derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown.
Outcome Measurements And Statistical Analysis:
Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model.
Results And Limitations:
Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant.
Conclusions:
This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation.
Patient Summary:
We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.
Insights
This study integrates proteogenomic data to reveal bladder cancer (BC) subtypes and identifies apoptosis induction as a potential therapy for FGFR3-mutated tumors. Further research into TRAIL-induced apoptosis for these bladder cancer patients is warranted.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Current molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer relies heavily on transcriptomic and genomic data.
- Bladder cancer (BC) exhibits significant heterogeneity, necessitating deeper molecular insights for improved classification and treatment.
Purpose of the Study:
- To perform proteogenomic analyses for a comprehensive understanding of BC heterogeneity.
- To identify molecular processes specific to BC subgroups and therapeutic outcomes.
- To explore potential therapeutic strategies for FGFR3-mutated bladder tumors.
Main Methods:
- Integrated proteomic, genomic, and transcriptomic data from 40 MIBC and 23 NMIBC cases.
- Utilized unsupervised proteomic grouping (uPGs) and pathway enrichment analyses.
- Investigated FGFR3 alterations in BC cell lines using genetic and pharmacological interventions, including TRAIL, birinapant, and erdafitinib.
Main Results:
- Identified five uPGs with similarities to transcriptomic subtypes, with uPG-E enriched in FGFR3 mutations.
- Discovered enrichment of apoptosis-related proteins in FGFR3-mutated tumors, a finding not evident from transcriptomics alone.
- Demonstrated that FGFR3 activation influences TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, enhanced by birinapant.
Conclusions:
- Proteogenomic analysis refines BC molecular classification, aiding patient management.
- Inducing apoptosis, particularly TRAIL-induced apoptosis, presents a promising therapeutic avenue for FGFR3-mutated bladder cancer.
- The findings warrant clinical investigation into TRAIL-induced apoptosis for specific bladder cancer patient subgroups.
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