Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis
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 th...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54246-6 |
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| author | F. A. Tucci R. Pennisi D. C. Rigiracciolo M. G. Filippone R. Bonfanti F. Romeo S. Freddi E. Guerrera C. Soriani S. Rodighiero R. H. Gunby G. Jodice F. Sanguedolce G. Renne N. Fusco P. P. Di Fiore G. Pruneri G. Bertalot G. Musi G. Vago D. Tosoni S. Pece |
| author_facet | F. A. Tucci R. Pennisi D. C. Rigiracciolo M. G. Filippone R. Bonfanti F. Romeo S. Freddi E. Guerrera C. Soriani S. Rodighiero R. H. Gunby G. Jodice F. Sanguedolce G. Renne N. Fusco P. P. Di Fiore G. Pruneri G. Bertalot G. Musi G. Vago D. Tosoni S. Pece |
| author_sort | F. A. Tucci |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e633256b3da04f098ba66dc7a3cd81cb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e633256b3da04f098ba66dc7a3cd81cb2024-12-08T12:37:18ZengNature PortfolioNature Communications2041-17232024-12-0115112410.1038/s41467-024-54246-6Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axisF. A. Tucci0R. Pennisi1D. C. Rigiracciolo2M. G. Filippone3R. Bonfanti4F. Romeo5S. Freddi6E. Guerrera7C. Soriani8S. Rodighiero9R. H. Gunby10G. Jodice11F. Sanguedolce12G. Renne13N. Fusco14P. P. Di Fiore15G. Pruneri16G. Bertalot17G. Musi18G. Vago19D. Tosoni20S. Pece21European Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSDepartment of Pathology, University of FoggiaEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSSchool of Pathology, University of MilanDepartment of Anatomy and Pathological Histology, APSSEuropean Institute of Oncology IRCCSSchool of Pathology, University of MilanEuropean Institute of Oncology IRCCSEuropean Institute of Oncology IRCCSAbstract 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.https://doi.org/10.1038/s41467-024-54246-6 |
| spellingShingle | F. A. Tucci R. Pennisi D. C. Rigiracciolo M. G. Filippone R. Bonfanti F. Romeo S. Freddi E. Guerrera C. Soriani S. Rodighiero R. H. Gunby G. Jodice F. Sanguedolce G. Renne N. Fusco P. P. Di Fiore G. Pruneri G. Bertalot G. Musi G. Vago D. Tosoni S. Pece Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis Nature Communications |
| title | Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis |
| title_full | Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis |
| title_fullStr | Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis |
| title_full_unstemmed | Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis |
| title_short | Loss of NUMB drives aggressive bladder cancer via a RHOA/ROCK/YAP signaling axis |
| title_sort | loss of numb drives aggressive bladder cancer via a rhoa rock yap signaling axis |
| url | https://doi.org/10.1038/s41467-024-54246-6 |
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