A new thinking: deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma

Cell & Bioscience

Research

Peng Luo¹  Chen Cai²  Le Qu³  Aimin Jiang⁴  Yu Fang⁴  Linhui Wang⁴  Zhenjie Wu⁴  Ming Chen⁵  Anbang Wang⁵  Bing Liu⁶ 

[1]Department of Oncology, Zhujiang Hospital, Southern Medical University, 510280, Guangzhou, China

[2]Department of Special Clinic, Changhai Hospital, Naval Medical University (Second Military Medical University), 200433, Shanghai, China

[3]Department of Urology, Affiliated Jinling Hospital, Medical School of Nanjing University, 210046, Nanjing, China

[4]Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), 200433, Shanghai, China

[5]Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), 200003, Shanghai, China

[6]Department of Urology, The Third Affiliated Hospital, Naval Medical University (Second Military Medical University), 201805, Shanghai, China

关键词: Copper induced cell death;    Pan-cancer;    Clear cell renal cell carcinoma;    Molecular subtypes;    Tumor immunity;   

DOI  :  10.1186/s13578-022-00948-7

 received in 2022-04-29, accepted in 2022-12-22,  发布年份 2022

来源: Springer

【 摘 要 】

RationaleRecent research has indicated that cuprotosis, or copper induced cell death, is a novel type of cell death that could be utilized as a new weapon for cancer management. However, the characteristics and implications of such signatures in cancers, especially in clear cell renal cell cancer (ccRCC), remain elusive.MethodsExpression, methylation, mutation, clinical information, copy number variation, functional implication, and drug sensitivity data at the pan-cancer level were collected from The Cancer Genome Atlas. An unsupervised clustering algorithm was applied to decipher ccRCC heterogeneity. Immune microenvironment construction, immune therapy response, metabolic pattern, and cancer progression signature between subgroups were also investigated.ResultsCuprotosis related genes were specifically downregulated in various cancer tissues compared with normal tissues and were correlated with hypermethylation and copy number variation. Cuprotosis scores were also dysregulated in tumor tissues, and we found that such a signature could positively regulate oxidative phosphorylation and Myc and negatively regulate epithelial mesenchymal translation and myogenesis pathways. CPCS1 (cuprotosis scores high) and CPCS2 (cuprotosis scores low) in ccRCC displayed distinctive clinical profiles and biological characteristics; the CPCS2 subtype had a higher clinical stage and a worse prognosis and might positively regulate cornification and epidermal cell differentiation to fuel cancer progression. CPCS2 also displayed a higher tumor mutation burden and low tumor stemness index, while it led to a low ICI therapy response and dysfunctional tumor immunity state. The genome-copy numbers of CPCS2, including arm- gain and arm- loss, were higher than those of CPCS1. The prognostic model constructed based on subgroup biomarkers exerted satisfactory performance in both the training and validation cohorts. In addition, overexpression of the copper death activator DLAT suppressed the malignant ability, including cell migration and proliferation, of renal cell lines in vitro and in vivo. Finally, activation of cuprotosis in tumors could enhance antitumor immunity through dsDNA-cGAS-STING signaling in ccRCC.ConclusionThe activation of cuprotosis might function as a promising approach among multiple cancers. The cuprotosis related signatures could reshape tumor immunity in the ccRCC microenvironment via cGAS-STING signal, thus activating tumor antigen-presenting process. Upregulation of DLAT expression in ccRCC cell lines could reactivate the copper death pattern and be treated as a suitable target for ccRCC.

【 授权许可】

CC BY   
© The Author(s) 2022

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