费城儿童医院Raphael J. Morscher研究小组近日取得一项新成果。经过不懈努力，他们揭示了通过饮食增强的多胺耗竭重编程神经母细胞瘤。该项研究成果发表在2025年9月24日出版的《自然》上。

在这里，该研究团队发现这种抑制可以通过饮食限制上游氨基酸底物而增强，从而导致Th-MYCN基位模型中致癌蛋白翻译的中断、肿瘤分化和深刻的生存获益。具体而言，不含精氨酸和脯氨酸的饮食减少了多胺前体鸟氨酸的数量，并增加了二氟甲基鸟氨酸对多胺的消耗。这种多胺耗损导致核糖体停滞，出乎意料的是，特别是在第三位有腺苷的密码子上。这类密码子在细胞周期基因中选择性富集，而在神经元分化基因中富集较少。在饮食和药物联合干预下，这些密码子的翻译受损，有利于促进分化的蛋白质组。这些结果表明，特定细胞程序的基因已经进化出了标志性的密码子偏好，从而能够响应代谢应激进行连贯的翻译重新布线，并且这一过程可以靶向激活儿科癌症的分化。

据悉，神经母细胞瘤是一种高度致命的儿童期肿瘤，起源于分化受阻的神经嵴细胞。像所有癌症一样，它的生长是由循环或局部生物合成获得的代谢物推动的。神经母细胞瘤依赖于局部多胺生物合成，抑制剂二氟甲基鸟氨酸已显示出临床活性。

附：英文原文

Title: Reprogramming neuroblastoma by diet-enhanced polyamine depletion

Author: Cherkaoui, Sarah, Turn, Christina S., Yuan, Yuan, Lu, Wenyun, Yang, Lifeng, McBride, Matthew J., Eigenmann, Caroline, Allen, George E., Panasenko, Olesya O., Zhang, Lu, Vu, Annette, Liu, Kangning, Li, Yimei, Gandhi, Om H., Surrey, Lea F., Kienast, Sandra D., Leidel, Sebastian A., Wierer, Michael, White, Eileen, Rabinowitz, Joshua D., Hogarty, Michael D., Morscher, Raphael J.

Issue&Volume: 2025-09-24

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.

DOI: 10.1038/s41586-025-09564-0

Source: https://www.nature.com/articles/s41586-025-09564-0