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<p>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 <i>Npm1</i> 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, <i>NPM1</i> expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring <i>NPM1</i> deletions exhibit preferential <i>TP53</i> 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 <i>KRAS</i>-mutant CRC, and hepatic cancers.</p>

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Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Georgios Kanellos,
  • Chiara Giacomelli,
  • Alexander Raven,
  • Nikola Vlahov,
  • Hu Jin,
  • Pauline Herviou,
  • Sudhir B. Malla,
  • Nadia Nasreddin,
  • Patricia P. Centeno,
  • Constantinos Alexandrou,
  • Kathryn Gilroy,
  • Rachel L. Baird,
  • Kathryn Pennel,
  • June Munro,
  • Joseph A. Waldron,
  • Holly Hall,
  • Leah Officer-Jones,
  • Sheila Bryson,
  • Douglas Strathdee,
  • Sergio Lilla,
  • Sara Zanivan,
  • Vivienne Morrison,
  • Colin Nixon,
  • Rachel A. Ridgway,
  • Crispin Miller,
  • John R. P. Knight,
  • Andrew D. Campbell,
  • Philip D. Dunne,
  • John Le Quesne,
  • Joanne Edwards,
  • Peter J. Park,
  • Martin Bushell,
  • Owen J. Sansom

摘要

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.