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

Abstract

Rationale Recent 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. Methods Expression, 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. Results Cuprotosis 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. Conclusion The 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.

Identification and validation of a novel risk model based on cuproptosis‑associated m6A for head and neck squamous cell carcinoma

“…The cGMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial component of innate immunity by responding to DNA triggers and orchestrating diverse immune responses that impact different stages of cancer development, including initiation and metastasis [ 59 ]. Cuproptosis has been shown to enhance cancer immunity by activating the cGAS-STING signaling pathway in clear cell renal cell carcinoma cells [ 60 ]. Moreover, in mouse tumor models, the combined use of cuproptosis inducers (elesclomol and CuCl2) with anti-PD-1 therapy synergistically increases levels of circulating CD8 + T cells.…”

Copper homeostasis and cuproptosis in cancer immunity and therapy

“…142,143 Cuproptosis has been found to enable to improve cancer immunity via cGAS-STING signaling in ccRCC. 79 The cGAS-STING activity is elevated in dendritic cells co-cultured with cuproptosisactivated ccRCC cells induced by elesclomol and Cucl 2 with a dose-dependent manner. Additionally, the intracellular activity of cGAMP is increased in dendritic cells, with the elevated levels of IL2, TNFα, IFNγ, and CXCL10/11 secreted by the medium supernatant from the co-cultured system.…”

“…Meanwhile, selective Cu 2+ chelator ammonium tetrathiomolybdate and suppressing DLAT expression effectively attenuate cuproptosis. Suppression of DLAT enables to attenuate malignant behaviors and tumor growth in several cancer types 78‐80 . The 26S proteasome non‐ATPase regulatory subunit 11 (PSMD11) interacts with ATP7A, DLAT, and PDHA1, thus modulating HCC progression 81 .…”

“…The cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) signaling is emerging as an essential innate immune signaling that, with subsequent engagement by DNA, facilitates diverse immune effector response enabling to influence virtually each aspect of carcinogenesis, from malignant conversion to metastases 142,143 . Cuproptosis has been found to enable to improve cancer immunity via cGAS‐STING signaling in ccRCC 79 . The cGAS‐STING activity is elevated in dendritic cells co‐cultured with cuproptosis‐activated ccRCC cells induced by elesclomol and Cucl 2 with a dose‐dependent manner.…”

“…Suppression of DLAT enables to attenuate malignant behaviors and tumor growth in several cancer types. [78][79][80] The 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) interacts with ATP7A, DLAT, and PDHA1, thus modulating HCC progression. 81 Except for cuproptosis, DLAT promotes pro-survival autophagy of HCC cells.…”