目的:胰腺导管腺癌(PDAC)由于其高异质性和侵袭性而提出了重大挑战。认识到划定分子亚型的紧迫性,我们的研究集中在PDAC中脂质代谢重塑的新兴领域,特别是探索与脂肪酸生物合成相关的预后潜力和分子分类。
方法:进行基因集变异分析(GSVA)和单样本基因集富集分析(ssGSEA)以评估PDAC中脂质代谢的失调。单变量cox分析和LASSO模块用于构建预后风险评分签名。通过基因本体论(GO)和京都基因和基因组百科全书(KEGG)富集分析和加权基因共表达网络分析(WGCNA)探索了不同风险组中基因表达的区别。酰基辅酶A合成酶长链家族成员5(ACSL5)的生物学功能,7-hub基因特征组中的关键基因,通过体外试验进行了验证。
结果:我们的研究确定了与脂肪酸生物合成相关基因(FRGs)相关的7-hub基因标签,为预后预测提供了可靠的工具。高FRGs评分组的预后较差,减少免疫细胞浸润,和更高的肿瘤突变负担。有趣的是,根据癌症药物敏感性基因组学(GDSC)数据库,该组对各种化合物的反应性增强。值得注意的是,ACSL5在PDAC中上调,对肿瘤进展至关重要。
结论:结论:我们的研究在PDAC中定义了两种新的基于脂肪酸生物合成的亚型,以不同的转录谱为特征。这些亚型不仅作为预后指标,但也提供了有关其转移倾向和治疗潜力的宝贵见解。
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis.
METHODS: Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays.
RESULTS: Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression.
CONCLUSIONS: In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.