2. Academic Validation
  3. Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis

Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis

  • Nat Commun. 2024 Dec 3;15(1):10378. doi: 10.1038/s41467-024-54246-6.
F A Tucci # 1 2,  R Pennisi # 1 3,  D C Rigiracciolo 1 4,  M G Filippone 1 5,  R Bonfanti 1,  F Romeo 1 5,  S Freddi 1 5,  E Guerrera 1,  C Soriani 1,  S Rodighiero 1,  R H Gunby 1,  G Jodice 1,  F Sanguedolce 6,  G Renne 1,  N Fusco 1 5,  P P Di Fiore 1 5,  G Pruneri 2 5 7,  G Bertalot 8 9,  G Musi 1 5,  G Vago 2 5,  D Tosoni 10,  S Pece 11 12
Affiliations

Affiliations

  • 1 European Institute of Oncology IRCCS, Milan, Italy.
  • 2 School of Pathology, University of Milan, Milan, Italy.
  • 3 Department of Oncology, University of Turin, Turin, Italy.
  • 4 IRCCS Scientific Institute San Raffaele, Milan, Italy.
  • 5 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
  • 6 Department of Pathology, University of Foggia, Foggia, Italy.
  • 7 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • 8 Department of Anatomy and Pathological Histology, APSS, Trento, Italy.
  • 9 Centre for Medical Sciences-CISMed, University of Trento, Trento, Italy.
  • 10 European Institute of Oncology IRCCS, Milan, Italy. daniela.tosoni@ieo.it.
  • 11 European Institute of Oncology IRCCS, Milan, Italy. salvatore.pece@ieo.it.
  • 12 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. salvatore.pece@ieo.it.
  • # Contributed equally.
PMID: 39627202 DOI: 10.1038/s41467-024-54246-6
Abstract

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.

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