铜驱动新陈代谢状态的重塑和透明细胞肾细胞癌的进展。

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-02-07 DOI:10.1158/2159-8290.CD-24-0187

Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska

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引用次数: 0

摘要

铜（Cu）是细胞色素 c 氧化酶（CuCOX）的辅助因子，是有氧线粒体呼吸不可或缺的物质。这项研究发现，晚期透明细胞肾细胞癌（ccRCC）会积累铜，并将其分配给CuCOX。我们采用了一系列正交方法，包括代谢组学、脂质组学、同位素标记的葡萄糖和谷氨酰胺通量分析以及肿瘤样本、细胞系、异种移植和 PDX 模型的转录组学，并结合基因和药物干预，探讨了 Cu 在 ccRCC 中的作用。Cu水平升高会刺激CuCOX的生物生成，提供生物能和生物合成益处，从而促进肿瘤生长。葡萄糖依赖性谷胱甘肽的产生补充了这一作用，促进了解毒并减轻了 Cu-H2O2 的毒性。单细胞 RNA 测序（scRNA-seq）和空间转录组学揭示了 ccRCC 进展过程中氧化代谢增加、谷胱甘肽和铜代谢改变以及 HIF 活性降低。因此，铜推动了生物能、生物合成和氧化还原平衡的综合致癌重塑，助长了ccRCC的生长，而这可以成为新治疗方法的靶点。

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Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma.

Significance: The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.