Cross-talk between cuproptosis and ferroptosis regulators defines the tumor microenvironment for the prediction of prognosis and therapies in lung adenocarcinoma

Abstract

Cuproptosis, a newly identified form of programmed cell death, plays vital roles in tumorigenesis. However, the interconnectivity of cuproptosis and ferroptosis is poorly understood. In our study, we explored genomic alterations in 1162 lung adenocarcinoma (LUAD) samples from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) cohort to comprehensively evaluate the cuproptosis regulators. We systematically performed a pancancer genomic analysis by depicting the molecular correlations between the cuproptosis and ferroptosis regulators in 33 cancer types, indicating cross-talk between cuproptosis and ferroptosis regulators at the multiomic level. We successfully identified three distinct clusters based on cuproptosis and ferroptosis regulators, termed CuFeclusters, as well as the three distinct cuproptosis/ferroptosis gene subsets. The tumor microenvironment cell-infiltrating characteristics of three CuFeclusters were highly consistent with the three immune phenotypes of tumors. Furthermore, a CuFescore was constructed and validated to predict the cuproptosis/ferroptosis pathways in individuals and the response to chemotherapeutic drugs and immunotherapy. The CuFescore was significantly associated with the expression of miRNA and the regulation of post-transcription. Thus, our research established an applied scoring scheme, based on the regulators of cuproptosis/ferroptosis to identify LUAD patients who are candidates for immunotherapy and to predict patient sensitivity to chemotherapeutic drugs.

Identification and validation of a novel cuproptosis-related stemness signature to predict prognosis and immune landscape in lung adenocarcinoma by integrating single-cell and bulk RNA-sequencing

“…In fact, a novel form of copper-dependent cell death that is triggered by copper ionophores, called cuproptosis, is accompanied by the accumulation of ROS and mitochondrial metabolism ( 13 , 14 ). Previous studies have identified several genes and lncRNAs related to cuproptosis in LUAD ( 20 , 21 , 45 – 47 ), and developed a cuproptosis signature that correlates with the prognosis and tumor microenvironment of LUAD patients ( 16 , 19 , 48 ). Therefore, cuproptosis may play an important role in LUAD and provide new insights into the treatment of CSCs.…”

Ferroptosis: emerging roles in lung cancer and potential implications in biological compounds

“…Next, the occurrence of ferroptosis is due to the production of ROS by excessive free Fe 2+ under the action of Fenton reaction, which produce lipid peroxidation caused by oxidized lipids. Cuproptosis is a newly discovered programmed cell death caused by Cu 2+ as well ( Shen et al, 2023b ). Finally, accumulated research has found that some biological compounds have multiple effects in controlling malignant tumors, such as inducing autophagy to prevent apoptosis of malignant tumor cells.…”

Regulation of Ferroptosis in Lung Adenocarcinoma

“…In addition, bioinformatics analyses have revealed a potential clinical connection between the FRGs and LUAD patients. A prognostic model integrating several FRGs was used to predict the prognosis, mutation burden, tumor microenvironment (TME) cell infiltration characteristics, immunotherapy effects, and chemotherapy sensitivities in patients with LUAD [32][33][34][35][36][37].…”