eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited treatment options. Although metabolic reprogramming is a hallmark of many cancers, including PDA, previous attempts to target metabolic changes therapeutically have been stymied by drug toxicity and tumour cell plasticity. Here, we show that PDA cells engage an eIF4F-dependent translation program that supports redox and central carbon metabolism. Inhibition of the eIF4F subunit, eIF4A, using the synthetic rocaglate CR-1-31-B (CR-31) reduced the viability of PDA organoids relative to their normal counterparts. In vivo, CR-31 suppresses tumour growth and extends survival of genetically-engineered murine models of PDA. Surprisingly, inhibition of eIF4A also induces glutamine reductive carboxylation. As a consequence, combined targeting of eIF4A and glutaminase activity more effectively inhibits PDA cell growth both in vitro and in vivo. Overall, our work demonstrates the importance of eIF4A in translational control of pancreatic tumour metabolism and as a therapeutic target against PDA. Overall design: RNA sequencing of polysome-associated mRNA and total mRNA of treated and untreated normal mouse organoids, as well as treated and untreated pancreatic ductal adenocarcinoma mouse organoids. Each condition and RNA source combination was replicated 3 times, leading to a total of 24 samples.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDA）是一种致死性恶性肿瘤，临床治疗选择极为有限。尽管代谢重编程是包括PDA在内的多数癌症的标志性特征，但此前靶向代谢变化的治疗尝试均因药物毒性与肿瘤细胞可塑性而遭遇阻碍。本研究证实，PDA细胞借助依赖真核翻译起始因子4F（eIF4F）的翻译程序，支持氧化还原与中心碳代谢过程。使用合成罗卡格莱特类化合物CR-1-31-B（CR-31）抑制真核翻译起始因子4A（eIF4A，eIF4F亚基），可降低PDA类器官的细胞存活率，且相较于正常对照类器官效果更为显著。体内实验表明，CR-31可抑制PDA基因工程小鼠模型的肿瘤生长，并延长其生存周期。令人意外的是，抑制eIF4A还可诱导谷氨酰胺还原性羧化反应。据此，联合靶向eIF4A与谷氨酰胺酶活性，可在体外与体内更高效地抑制PDA细胞增殖。综上，本研究证实了eIF4A在胰腺肿瘤代谢翻译调控中的关键作用，以及其作为抗PDA治疗靶点的应用价值。整体实验设计：对经处理与未处理的正常小鼠类器官，以及经处理与未处理的胰腺导管腺癌小鼠类器官的多聚体结合mRNA与总mRNA进行RNA测序。每个实验条件与RNA来源的组合均重复3次，最终共计获得24个测序样本。