biostudies-literatureTucci FAMinistero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)Ministero della Salute (Ministry of Health, Italy)Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)10378https://www.ebi.ac.uk/biostudies/studies/S-EPMC11615365biostudies-literatureUnknown15(1)Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-depenNature communicationsLoss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.PMC11615365MIUR-PRIN20175x1000 fundsIG 23049MIUR/PRIN2020Ricerca CorrenteIG 23060RF-2021-12373957RF-2016-02361540Fusco NFreddi SGunby RHSanguedolce FRenne GPennisi RFilippone MGRigiracciolo DCRodighiero SPece SGuerrera EMusi GBertalot GDi Fiore PPVago GPruneri GTosoni DJodice GRomeo FBonfanti RSoriani CTucci FAfalseLoss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis.Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-depen2024-01-01T00:00:00Z2024 Dec2025-04-04T01:06:34.211Z2025-04-04T01:06:34.211ZS-EPMC116153653962720210.1038/s41467-024-54246-6