Reprogramming neuroblastoma by diet-enhanced polyamine depletion

Sarah Cherkaoui, Christina S. Turn, Yuan Yuan, Wenyun Lu, Lifeng Yang, Matthew J. McBride, Caroline Eigenmann, George E. Allen, Olesya O. Panasenko, Lu Zhang, Annette Vu, Kangning Liu, Yimei Li, Om H. Gandhi, Lea F. Surrey, Sandra D. Kienast, Sebastian A. Leidel, Michael Wierer, Eileen White, Joshua D. Rabinowitz (), Michael D. Hogarty () and Raphael J. Morscher ()
Additional contact information
Sarah Cherkaoui: University of Zurich
Christina S. Turn: Children’s Hospital of Philadelphia
Yuan Yuan: University of Zurich
Wenyun Lu: Princeton University
Lifeng Yang: Princeton University
Matthew J. McBride: Princeton University
Caroline Eigenmann: University of Zurich
George E. Allen: Faculty of Medicine
Olesya O. Panasenko: Faculty of Medicine
Lu Zhang: Princeton University
Annette Vu: Children’s Hospital of Philadelphia
Kangning Liu: Children’s Hospital of Philadelphia
Yimei Li: Children’s Hospital of Philadelphia
Om H. Gandhi: Children’s Hospital of Philadelphia
Lea F. Surrey: Perelman School of Medicine at the University of Pennsylvania
Sandra D. Kienast: University of Zurich
Sebastian A. Leidel: University of Bern
Michael Wierer: University of Copenhagen
Eileen White: Princeton University
Joshua D. Rabinowitz: Princeton University
Michael D. Hogarty: Children’s Hospital of Philadelphia
Raphael J. Morscher: University of Zurich

Nature, 2025, vol. 646, issue 8085, 707-715

Abstract: Abstract Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09564-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:646:y:2025:i:8085:d:10.1038_s41586-025-09564-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09564-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().