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。
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.
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.