Nucleophosmin sustains WNT-driven cell proliferation and tumor initiation in vivo

Nucleophosmin (NPM1) is a nucleolar protein frequently overexpressed in many solid tumours with little known about its functional role to support carcinogenesis. Here, we identify Npm1 as a commonly upregulated gene following Apc loss in highly proliferative tissues, and high expression correlates with increased proliferation in CRC patients. We show that NPM1 is dispensable for adult epithelial tissue homeostasis, however, it has a profound effect on WNT-driven intestinal and liver tumourigenesis, leading to reduced proliferation and extension of survival. Mechanistically, NPM1 depletion triggers integrated stress response (ISR) and p53 pathway activation. P53 deletion, or inhibition of the ISR effects, rescue proliferation following NPM1 loss. Overall, our results demonstrate that NPM1 supports WNT-driven cell proliferation and tumour initiation by attenuating p53 pathway activation or induction of ISR. Being dispensable for homeostasis, NPM1 presents as a promising target for cancer therapy in WNT-driven tumours with functional p53, including difficult to treat KRAS-mutant CRC and hepatic cancers. Overall design: To investigate the role of Nucleophosmin (Npm1) on colorectal cancer, we conditionally deleted it in an APC null/KRAS mutant cancer model. Epithelial extracts three days post-KO were harvested from mice. Ribo-seq and total cytoplasmic RNA sequencing were performed to address the effects on translation as well as transcript levels. The experiment was performed in four independent mice. Replicates are indicated by _1/_2/_3/_4. CRUK Scotland Institute Mouse IDs are indicated.