Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation
Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.
Authors
- Chiara Giacomelli (ORCID: https://orcid.org/0000-0003-1466-1371)
- Martin Bushell (ORCID: https://orcid.org/0000-0001-9938-2691)
- Alexander Raven (ORCID: https://orcid.org/0000-0003-4409-9543)
- June Munro
- Sudhir B. Malla (ORCID: https://orcid.org/0000-0001-5862-3815)
- Patricia P. Centeno (ORCID: https://orcid.org/0000-0002-8754-7812)
- Peter J. Park (ORCID: https://orcid.org/0000-0001-9378-960X)
- Pauline Herviou (ORCID: https://orcid.org/0009-0008-1927-1843)
- Sara Zanivan (ORCID: https://orcid.org/0000-0002-9880-9099)
- Georgios Kanellos (ORCID: https://orcid.org/0000-0002-2467-4523)
- Nikola Vlahov (ORCID: https://orcid.org/0009-0002-8649-6109)
- H. G. HALL (ORCID: https://orcid.org/0000-0003-2779-2565)
- Hu Jin (ORCID: https://orcid.org/0000-0002-8657-5686)
- Sheila Bryson (ORCID: https://orcid.org/0000-0003-0800-3129)
- Kathryn Gilroy (ORCID: https://orcid.org/0000-0003-4607-194X)
- Colin Nixon (ORCID: https://orcid.org/0000-0002-8085-2160)
- Joseph A. Waldron (ORCID: https://orcid.org/0000-0002-5682-5314)
- Rachel A. Ridgway (ORCID: https://orcid.org/0000-0003-0198-8244)
- John Le Quesne (ORCID: https://orcid.org/0000-0003-3552-7446)
- Nadia Nasreddin (ORCID: https://orcid.org/0000-0002-3025-6213)
- Sérgio Lilla (ORCID: https://orcid.org/0000-0003-3142-7640)
- Andrew D. Campbell (ORCID: https://orcid.org/0000-0003-3930-1276)
- Owen J. Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Douglas Strathdee (ORCID: https://orcid.org/0000-0003-2959-4327)
- Joanne Edwards (ORCID: https://orcid.org/0000-0002-7192-6906)
- Philip D. Dunne (ORCID: https://orcid.org/0000-0001-9160-283X)
- Crispin Miller (ORCID: https://orcid.org/0000-0003-4341-1283)
- Rachel Pennie (ORCID: https://orcid.org/0009-0001-4796-7388)
- Constantia Alexandrou (ORCID: https://orcid.org/0000-0001-9136-3621)
- Kathryn A.F. Pennel (ORCID: https://orcid.org/0000-0003-0186-1331)
- Leah Officer-Jones (ORCID: https://orcid.org/0000-0002-3690-2386)
- John R. P. Knight (ORCID: https://orcid.org/0000-0002-8771-5484)
- Vivienne Morrison (ORCID: https://orcid.org/0009-0009-1022-8969)
Institutions
- Queen's University Belfast (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Cancer Research UK (GB)
- University of Manchester (GB)
- Cancer Research UK Manchester Institute (GB)
- Queen Elizabeth University Hospital (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1038/s41588-025-02408-7
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00