Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

IF 11.7 1区医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2025-01-21 Epub Date: 2024-12-20 DOI:10.1016/j.xcrm.2024.101878

Marjolein M G Kes, Francisco Morales-Rodriguez, Esther A Zaal, Terezinha de Souza, Natalie Proost, Marieke van de Ven, Marry M van den Heuvel-Eibrink, Jeroen W A Jansen, Celia R Berkers, Jarno Drost

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Abstract

Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

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患者来源的类器官代谢谱揭示了核苷酸合成在恶性横纹肌样肿瘤中的代谢易感性。

恶性横纹肌样肿瘤（MRT）是最具侵袭性的儿童癌症之一，目前尚无有效的治疗方案。细胞代谢的重编程是癌症的一个重要标志，各种基于代谢的药物被批准作为癌症治疗。在这项研究中，我们使用患者来源的肿瘤类器官（类肿瘤）来绘制几种儿科癌症的代谢景观。结合基因表达分析和代谢物谱分析，我们发现核苷酸生物合成是MRT的一个特殊脆弱性。用新的核苷酸合成抑制剂甲氨蝶呤（MTX）和BAY-2402234治疗MRT类肿瘤可降低MRT类肿瘤中的核苷酸水平并诱导细胞凋亡。最后，我们在MRT患者来源的异种移植（PDX）小鼠模型中证明了MTX的体内疗效。我们的研究揭示了核苷酸生物合成作为一种mrt特异性代谢脆弱性，它最终可以为患有这种致命的儿科恶性肿瘤的儿童提供更好的治疗选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.