Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou 014030, China; School of Basic Medicine, Baotou Medical College, Baotou 014040, China.
Translational Medicine Center, Baotou Medical College, Baotou 014040, China.
Int Immunopharmacol. 2024 Aug 20;137:112433. doi: 10.1016/j.intimp.2024.112433. Epub 2024 Jun 12.
Gastric cancer (GC) is a refractory malignant tumor with high tumor heterogeneity, a low rate of early diagnosis, and poor patient prognosis. Lipid metabolism reprogramming plays a critical role in tumorigenesis and progression, but its prognostic role and regulatory mechanism in GC are rarely studied. Thus, the identification of signatures related to lipid metabolism is necessary and may present a new avenue for improving the overall prognosis of GC.
Lipid metabolism-associated genes (LMAGs) with differential expression in tumor and tumor-adjacent tissue were acquired to identify lipid metabolism-associated subtypes. The differentially expressed genes (DEGs) between the two clusters were then utilized for prognostic analysis and signature construction. Additionally, pathway enrichment analysis and immune cell infiltration analysis were employed to identify the characteristics of the prognostic model. Further analyses were conducted at the single-cell level to better understand the model's prognostic mechanism. Finally, the prediction of immunotherapy response was used to suggest potential treatments.
Two lipid metabolism-associated subtypes were identified and 9 prognosis-related genes from the DEGs between the two clusters were collected for the construction of the prognostic model named lipid metabolism-associated signature (LMAS). Then we found the low LMAS patients with favorable prognoses were more sensitive to ferroptosis in the Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD). Meanwhile, the tumor cells exhibiting high levels of lipid peroxidation and accumulation of reactive oxygen species (ROS) in single-cell levels were primarily enriched in the low LMAS group, which was more likely to induce ferroptosis. In addition, endothelial cells and cancer-associated fibroblasts (CAFs) facilitated tumor angiogenesis, proliferation, invasion, and metastasis through endothelial-mesenchymal transition (EndMT), affecting the prognosis of the patients with high LMAS scores. Moreover, CD1C CD141 dendritic cells (DCs) also secreted pro-tumorigenic cytokines to regulate the function of endothelial cells and CAFs. Finally, the patients with low LMAS scores might have better efficacy in immunotherapy.
A LMAS was constructed to guide GC prognosis and therapy. Meanwhile, a novel anti-tumor effect was found in lipid metabolism reprogramming of GC which improved patients' prognosis by regulating the sensitivity of tumor cells to ferroptosis. Moreover, EndMT may have a negative impact on GC prognosis.
胃癌（GC）是一种难治性恶性肿瘤，具有肿瘤异质性高、早期诊断率低、患者预后差等特点。脂质代谢重编程在肿瘤发生和进展中起着关键作用，但 GC 中其预后作用和调控机制研究甚少。因此，鉴定与脂质代谢相关的特征对于改善 GC 的总体预后是必要的，可能为改善 GC 的总体预后提供新的途径。
获取肿瘤组织和肿瘤旁组织中差异表达的脂质代谢相关基因（LMAGs），以鉴定脂质代谢相关亚型。然后利用两个聚类之间的差异表达基因（DEGs）进行预后分析和特征构建。此外，还进行了通路富集分析和免疫细胞浸润分析，以鉴定预后模型的特征。在单细胞水平上进行进一步分析，以更好地理解模型的预后机制。最后，预测免疫治疗反应，为潜在的治疗提供建议。
鉴定出两个脂质代谢相关亚型，并从两个聚类的 DEGs 中收集了 9 个与预后相关的基因，用于构建名为脂质代谢相关特征（LMAS）的预后模型。然后我们发现，在癌症基因组图谱胃癌（TCGA-STAD）中，低 LMAS 患者具有较好的预后，对铁死亡更为敏感。同时，在单细胞水平上，脂质过氧化水平较高且活性氧（ROS）积累较多的肿瘤细胞主要富集在低 LMAS 组中，更容易诱导铁死亡。此外，内皮细胞和癌相关成纤维细胞（CAFs）通过内皮间充质转化（EndMT）促进肿瘤血管生成、增殖、侵袭和转移，影响高 LMAS 评分患者的预后。此外，CD1C CD141 树突状细胞（DC）也分泌促肿瘤细胞因子来调节内皮细胞和 CAFs 的功能。最后，低 LMAS 评分的患者可能对免疫治疗更有效。
构建了一个 LMAS 来指导 GC 的预后和治疗。同时，在 GC 的脂质代谢重编程中发现了一种新的抗肿瘤作用，通过调节肿瘤细胞对铁死亡的敏感性改善了患者的预后。此外，EndMT 可能对 GC 的预后有负面影响。
