학술논문
Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors.
Document Type
Academic Journal
Author
Groeneveld CS; Equipe 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.; Sanchez-Quiles V; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France.; Dufour F; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Inovarion, Paris, France.; Shi M; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Dingli F; Centre de Recherche, CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France.; Nicolle R; Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Université Paris Cité, Paris, France.; Chapeaublanc E; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France.; Poullet P; INSERM U900, MINES ParisTech, Institut Curie, PSL Research University, Paris, France.; Jeffery D; Urology Medico-Scientific Program, Department of Translational Research, Institut Curie, PSL Research University, Paris, France.; Krucker C; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France.; Maillé P; Département de Pathologie, Hôpital Henri Mondor, APHP, Créteil, France.; Vacherot F; Université Paris Est Créteil, TRePCa, Créteil, France.; Vordos D; Service d'Urologie, Hôpital Henri Mondor, APHP, Créteil, France.; Benhamou S; Gustave Roussy, INSERM U1018, Villejuif, France.; Lebret T; Service d'Urologie, Hôpital Foch, UVSQ, Université Paris-Saclay, Suresnes, France.; Micheau O; INSERM, LNC UMR1231, Université Bourgogne Franche-Comté, Dijon, France.; Zinovyev A; INSERM U900, MINES ParisTech, Institut Curie, PSL Research University, Paris, France.; Loew D; Centre de Recherche, CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France.; Allory Y; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France; Department of Pathology, Institut Curie, UVSQ, Université Paris-Saclay, Saint-Cloud, France.; de Reyniès A; Centre de Recherche des Cordeliers, AP-HP, Université Paris Cité, Paris, France.; Bernard-Pierrot I; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France.; Radvanyi F; Equipe labellisée Ligue Contre le Cancer, CNRS, UMR144, Institut Curie, PSL Research University, Paris, France. Electronic address: francois.radvanyi@curie.fr.
Source
Publisher: Elsevier Science Country of Publication: Switzerland NLM ID: 7512719 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7560 (Electronic) Linking ISSN: 03022838 NLM ISO Abbreviation: Eur Urol Subsets: MEDLINE
Subject
Language
English
Abstract
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.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)