Loss 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-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies.
Authors
- Giuseppe Renne (ORCID: https://orcid.org/0000-0003-4484-1832)
- Maria Grazia Filippone
- Francesco Romeo (ORCID: https://orcid.org/0000-0002-0182-3100)
- Francesco Tucci (ORCID: https://orcid.org/0000-0001-6247-5392)
- Francesca Sanguedolce (ORCID: https://orcid.org/0000-0001-7459-3521)
- Damiano Cosimo Rigiracciolo (ORCID: https://orcid.org/0000-0003-1161-6380)
- Daniela Tosoni (ORCID: https://orcid.org/0000-0003-4443-1059)
- Giovanni Bertalot (ORCID: https://orcid.org/0000-0002-4862-7705)
- Nicola Fusco (ORCID: https://orcid.org/0000-0002-9101-9131)
- Pier Paolo Di Fiore (ORCID: https://orcid.org/0000-0002-2252-0950)
- Stefano Freddi (ORCID: https://orcid.org/0000-0003-4263-3060)
- Chiara Soriani (ORCID: https://orcid.org/0000-0003-4363-6597)
- Gennaro Musi (ORCID: https://orcid.org/0000-0003-0833-9183)
- Rosalind H. Gunby (ORCID: https://orcid.org/0000-0002-4359-3884)
- Salvatore Pece (ORCID: https://orcid.org/0000-0003-1764-3929)
- Simona Rodighiero (ORCID: https://orcid.org/0000-0003-4236-7823)
- R. Bonfanti
- Giancarlo Pruneri (ORCID: https://orcid.org/0000-0002-7963-7172)
- Rosa Pennisi (ORCID: https://orcid.org/0000-0001-6542-7898)
- G. Vago
- Giovanna Jodice
- Elisa Guerrera
Institutions
- University of Foggia (IT)
- Vita-Salute San Raffaele University (IT)
- University of Milan (IT)
- University of Trento (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- University of Turin (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-03
- DOI
- https://doi.org/10.1038/s41467-024-54246-6
- Citations
- 9
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 2.93
Funders
- Università degli Studi di Milano
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro