Nucleophosmin supports WNT-driven hyperproliferation and tumour initiation

Nucleophosmin (NPM1), a nucleolar protein frequently mutated in haematopoietic malignancies, is overexpressed in several solid tumours with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated following APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumourigenesis. 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 anti-tumourigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumourigenesis by attenuating the integrated stress response (ISR) and p53 activation. Notably, NPM1 expression correlates with elevated WNT signalling and proliferation in human colorectal cancer (CRC), while CRCs harbouring 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 tumours, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.