State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China.
Cell Oncol (Dordr). 2024 Aug;47(4):1475-1491. doi: 10.1007/s13402-024-00953-7. Epub 2024 May 16.
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.
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.
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.
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.
胰腺导管腺癌（PDAC）由于其高度异质性和侵袭性，构成了重大挑战。鉴于明确界定分子亚型的紧迫性，我们的研究聚焦于 PDAC 中脂质代谢重塑这一新兴领域，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。
采用基因集变异分析（GSVA）和单样本基因集富集分析（ssGSEA）评估 PDAC 中脂质代谢的失调。采用单变量 cox 分析和 LASSO 模块构建预后风险评分特征。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析和加权基因共表达网络分析（WGCNA）探讨不同风险组之间的基因表达差异。通过体外实验验证酰基辅酶 A 合成酶长链家族成员 5（ACSL5）这一 7 个关键基因特征面板内关键基因的生物学功能。
我们的研究确定了一个与脂肪酸生物合成相关基因（FRGs）相关的 7 个关键基因特征，为预后预测提供了一个强大的工具。高 FRGs 评分组显示预后较差，免疫细胞浸润减少，肿瘤突变负担增加。有趣的是，根据癌症基因组药物敏感性（GDSC）数据库，该组对各种化合物表现出更强的反应性。值得注意的是，ACSL5 在 PDAC 中上调，并且对肿瘤进展至关重要。
总之，我们的研究在 PDAC 中定义了两个基于新脂肪酸生物合成的亚型，其特征在于不同的转录谱。这些亚型不仅作为预后指标，而且为其转移倾向和治疗潜力提供了有价值的见解。
