# Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation

## TL;DR

NPM1 supports tumor growth in WNT-driven cancers by reducing stress responses and p53 activation, making it a potential target for treatment.

## Contribution

NPM1 is identified as a novel WNT effector that sustains tumorigenesis by suppressing stress responses and p53 activation.

## Key findings

- NPM1 is upregulated in WNT-driven intestinal and liver tumorigenesis.
- NPM1 loss triggers protein synthesis stress and p53 activation.
- NPM1 deletions correlate with TP53 inactivation in colorectal cancer.

## Abstract

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.

Npm1 promotes tumor formation via attenuating the integrated stress response and p53 activation in mouse WNT-driven intestinal and liver tumorigenesis.