The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
Front Immunol. 2022 Jun 23;13:872910. doi: 10.3389/fimmu.2022.872910. eCollection 2022.
Metabolic reprogramming is a novel method for the treatment of malignant tumors. The exploration of metabolism procedures between radiosensitive and radioresistant tumors may provide novel perspectives for lung adenocarcinoma (LUAD) patients after radiation therapy. In our study, metabolic reprogramming and immune response changes were found between radioresistant cell line (A549RR) and its parent cells (A549) using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Nucleotide/amino acid, lipid, and glucose metabolic process, including Alanine, aspartate and glutamate metabolism, Tryptophan/Tyrosine metabolism, Butanoate metabolism, Purine/Pyrimidine metabolism, were screened out. Then molecular signatures database and The Cancer Genome Atlas Program (TCGA) lung adenocarcinoma datasets were used to identify metabolism-related genes (MRGs) between radiosensitive and radioresistant lung adenocarcinoma (LUAD) cells. A metabolism-based prognostic model, receiver operating characteristic (ROC) curve and nomogram were constructed using Metabolism Score calculated by 14 metabolism-related genes (MRGs). Three independent public datasets, (GSE72094, GSE3141, GSE8894) and one immunotherapy cohort (IMvigor210) were used as external validation cohorts. Expression of 14 hub genes in cells, normal and LUAD specimens were explored by Human Protein Atlas, TIMER2.0 and RT-qPCR. Patients with low-Metabolism Scores were correlated with longer survival times, higher response rates to immune checkpoint inhibitors (ICIs), different immune cell infiltrations and drug vulnerability. Our study demonstrated a comprehensive landscape between radiosensitive and radioresistant LUAD, and provide novel targets for NSCLC, especially those patients received radiation therapy. Moreover, this metabolism-based prognostic model may help to investigate connections between radiosensitivity, immune response, metabolic reprogramming, and patients' prognosis.
代谢重编程是治疗恶性肿瘤的一种新方法。探索放射敏感和放射抵抗肿瘤之间的代谢过程可能为放射治疗后的肺腺癌（LUAD）患者提供新的视角。在我们的研究中，使用基因本体论和京都基因与基因组百科全书（KEGG）通路分析发现，在耐辐射细胞系（A549RR）及其亲本细胞（A549）之间存在代谢重编程和免疫反应变化。筛选出核苷酸/氨基酸、脂质和葡萄糖代谢过程，包括丙氨酸、天冬氨酸和谷氨酸代谢、色氨酸/酪氨酸代谢、丁酸代谢、嘌呤/嘧啶代谢。然后使用分子特征数据库和癌症基因组图谱计划（TCGA）肺腺癌数据集，鉴定放射敏感和放射抵抗肺腺癌（LUAD）细胞之间的代谢相关基因（MRGs）。使用由 14 个代谢相关基因（MRGs）计算得出的代谢评分构建了基于代谢的预后模型、接收器工作特征（ROC）曲线和列线图。三个独立的公共数据集（GSE72094、GSE3141、GSE8894）和一个免疫治疗队列（IMvigor210）被用作外部验证队列。通过人类蛋白质图谱、TIMER2.0 和 RT-qPCR 研究了 14 个核心基因在细胞、正常和 LUAD 标本中的表达。低代谢评分患者与较长的生存时间、对免疫检查点抑制剂（ICIs）更高的反应率、不同的免疫细胞浸润和药物易感性相关。我们的研究展示了放射敏感和放射抵抗 LUAD 之间的综合景观，并为 NSCLC 提供了新的靶点，特别是那些接受放射治疗的患者。此外，基于代谢的预后模型可能有助于研究放射敏感性、免疫反应、代谢重编程和患者预后之间的联系。
