Unraveling the potential of senescence-related genes in guiding clinical therapy of lung adenocarcinoma patients

Abstract

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer. In recent years, cell senescence emerges as a potential therapeutic target of cancer therapy. However, the role of cell senescence in LUAD has not been comprehensively unveiled. One single cell RNA sequencing (scRNA-seq) dataset (GSE149655) and two bulk RNA-seq datasets (TCGA and GSE31210) of LUAD were included. Seurat R package was used to process scRNA-seq data and identify immune cell subgroups. Single sample gene set enrichment analysis (ssGSEA) was performed to calculate enrichment score of senescence-related pathways. Senescence-based molecular subtyping for LUAD samples was conducted through unsupervised consensus clustering. pRRophetic package was introduced to analysis drug sensitivity. The senescence-associated risk model was established using univariate regression and stepAIC methods. Western blot, RT-qPCR, immunofluorescence assay and CCK-8 were used to explore the effect of CYCS in LUAD cell lines. Malignant immune cells had remarkedly higher enrichment of senescence-related pathways than non-malignant cells. P53 signaling and DNA damage telomere stress induced senescence pathways were found to be significantly activated in LUAD samples compared with normal samples. We identified two clusters (clust1 and clust2) based on senescence-related genes. Clust1 had severe genomic instability, aggravated senescent features, and low immune and stromal infiltration. The senescence-associated risk model including CASP9, CHEK1, CYCS, SERPINE1, SESN2, TP53I3, LMNB1, RAD50 and TERF2IP, was effective to distinguish high- and low-risk groups. Moreover, low-risk group exhibited sensitive responses to immunotherapy and chemotherapeutic drugs. In vitro experiments results showed that CYCS expression was increased and promoted cell viability in LUAD cell lines. This study explored the important role of senescence in LUAD progression, and confirmed the potential of senescence-related genes in predicting LUAD prognosis and response to immunotherapy and chemotherapy.

Keywords: Cell cycle; Cell senescence; Immunotherapy; Lung adenocarcinoma; Risk model; Tumor microenvironment.