Abstract
Bladder cancer is one of the most common malignancies worldwide, impacting public health systems due to its high rate of recurrence. Metabolic alterations enable the identification of novel, needed prognostic markers and therapeutic vulnerabilities for precision oncology. Here, we use a systems metabolomics approach that integrates metabolic functional data with multi-omics, transcriptomics and metabolomics, through biostatistics and mathematical modelling to characterise metabolic rearrangements associated with FGFR3 oncogenic activation, one of the most frequent lesions in bladder cancer. The analyses conducted on a panel of five human bladder cancer cell lines reveal a significant correlation between FGFR3 alterations and the acquisition of a predominantly oxidative, poorly migratory phenotype, regardless of tumour progression. These preclinical results, validated through FGFR3 and oxidative phosphorylation pharmacological inhibition, and computational analysis on bladder cancer cell line and patient publicly available datasets, support the therapeutic potential of targeting oxidative metabolism in FGFR3-altered tumours, including more aggressive subtypes.
Acknowledgements
The authors would like to thank Fondazione Umberto Veronesi for supporting G.D. through 2025 scholarship. The authors would also like to thank SYSBIO/ISBE.IT Center of Systems Biology, particularly Professor Lilia Alberghina, and the Project of Excellence CHRONOS (CHRonical multifactorial disorders explored by NOvel integrated Strategies) of the Department of Biotechnology and Biosciences, University of Milano-Bicocca, for providing advanced technologies used in this study. The authors acknowledge the support of the PROPOSTA PROGETTUALE IR0000010 ELIXIRxNEXTgenIT-ELIXIR × NextGenerationIT: Consolidamento dell’Infrastruttura Italiana per i Dati Omici e la Bioinformatica-ElixirxNextGenIT”—CUP B53C22001800006, for providing the strategic infrastructure for omics data and bioinformatics. R.P. acknowledges the support of the Italian MUR Dipartimenti di Eccellenza 2023-2027 (l. 232/2016, art. 1, commi 314 - 337). Some images in the graphical abstract has been provided by Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Original elements were customised and adapted for the final composition, including modifications to colour, scaling and cropping. Declaration of generative AI and AI-assisted technologies in the writing process: during the preparation of this work, the authors used ChatGPT to improve the language and readability of some sentences of the manuscript. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Funding
E.S. and M.V. disclose support for the research of this work from the Italian Ministry of University and Research (MIUR) (Research facilitation fund - Fondo per le Agevolazioni alla Ricerca—FAR). M.V. discloses support for the research of this work from the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 871277). E.S. through Department of Biotechnology and Biosciences, and R.P. through Department of Medicine and Surgery, University of Milano-Bicocca, disclose support for the research of this work from the European Union - NextGenerationEU through the Italian Ministry of University and Research (PNRR - M4C2-I1.3 Project PE_00000019 “HEAL ITALIA”). D.O.C. discloses support for the research of this work from Collezione Nazionale di Composti Chimici e Centro Screening (CNCCS) Consortium, Project B, Sp2, WP9 “Metabolomica.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Ducci, G., Ciufolini, G., Campioni, G. et al. FGFR3 oncogenic activation drives oxidative metabolic reprogramming in bladder cancer: a systems metabolomics approach. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10356-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s42003-026-10356-z
