Targeting lipid synthesis and NADPH regeneration in cancer

肝脏脂肪生成是一个重要的细胞过程，它允许脂肪酸的重新合成，用于能量储存，膜生物合成和信号分子的生产。我们现在可以证明，由肝X受体α (LXRα)激活引发的脂肪生成增强代表了一种潜在的治疗肝癌（HCC）的新策略。肝癌小鼠模型和人、鼠肝癌细胞的治疗研究表明，LXRα的药理刺激联合同时阻断Raf激酶可导致肝癌细胞脂质积累和死亡，延长荷瘤小鼠的生存期。我们观察到小鼠对LXRα激活的耐受性良好，这表明有一个治疗窗口期，这种治疗方法是可行的。有趣的是，我们发现Raf抑制剂和肝癌药物索拉非尼是一种中度LXRα激活剂，并且可以证明增强的LXRα信号有助于其疗效。然而，通过使用LXRα激动剂治疗，充分激活LXRα，极大地改善了索拉非尼在HCC中的治疗效果。我们还获得证据表明，抑制脂质合成可能是治疗癌症的有效策略。我们可以证明，HCC细胞含有不同的致癌驱动因子（Nras, Akt），表现出特定的代谢表型，Akt驱动的肝癌细胞选择性地依赖醋酸酯合成乙酰辅酶a。在akt驱动的hcc中，抑制乙酰辅酶a合成酶2 (Acss2)，即催化该反应的酶，改变醋酸代谢和组蛋白乙酰化，降低细胞活力。此外，我们还进行了功能遗传筛选，以确定肝癌中可能代表新的治疗靶点的额外代谢脆弱性。在这个提议中，我们希望应用详细的体外和体内遗传和代谢分析来研究肝癌细胞如何受到脂肪生成途径的药理学和遗传操作的影响。我们希望表征LXRα诱导肝癌的细胞应激反应，并阐明定义观察到的治疗窗口的分子机制。此外，我们希望评估Raf在LXRα介导的细胞应激诱导中的作用，并确定Raf信号通路中与HCC中LXRα活化的协同反应有关的成分。我们还将确定Acss2在肝癌中的重要作用，并确定由Acss2依赖的醋酸代谢调节控制的细胞过程。为此，我们将研究Acss2抑制对脂质合成和通过组蛋白乙酰化进行表观遗传调控的影响。此外，我们将描述不同HCC基因型中新发现的代谢脆弱性，以评估其作为肝癌治疗靶点的潜力。

Hepatic lipogenesis is an essential cellular process that allows for the de novo synthesis of fatty acids for energy storage, membrane biosynthesis and production of signaling molecules. We could now show that an enhanced lipogenesis triggered by an activation of the Liver X receptor alpha (LXRα) represents a potential new therapeutic strategy against liver cancer (HCC). Treatment studies in liver cancer mouse models and in human and murine HCC cells revealed that pharmacological stimulation of LXRα in combination with a simultaneous blockade of the Raf kinase results in lipid accumulation and death of liver cancer cells and prolongs survival of tumor bearing mice. We observed that LXRα activation was in general well tolerated by mice, indicating that a therapeutic window enables the feasibility of such a therapeutic approach. Interestingly, we identified the Raf inhibitor and liver cancer drug Sorafenib as a moderate LXRα activator, and could show that enhanced LXRα signaling contributes to its efficacy. However, full activation of LXRα by treatment with established pharmacological LXRα agonists strongly improved the therapeutic outcome of Sorafenib in HCC.We also obtained evidence that inhibition of lipid synthesis can be an effective strategy for cancer treatment. We could show that HCC cells harboring different oncogenic drivers (Nras, Akt) exhibit specific metabolic phenotypes, with Akt-driven liver cancer cells selectively depending on acetate for the synthesis of acetyl-CoA. Inhibition of Acetyl-CoA synthetase 2 (Acss2), the enzyme catalyzing this reaction, altered acetate metabolism and histone acetylation, and reduced cell viability in Akt-driven HCCs. Moreover, we have performed functional genetic screens to identify additional metabolic vulnerabilities in liver cancer that may represent novel therapeutic targets.Within this proposal, we want to apply detailed genetic and metabolic analyses in vitro and in vivo to investigate how liver cancer cells are affected by pharmacological and genetic manipulation of lipogenic pathways. We want to characterize the cellular stress response induced by LXRα induction in liver cancer and elucidate the molecular mechanisms defining the observed therapeutic window. Furthermore, we want to evaluate the role of Raf in LXRα mediated cellular stress induction and identify those components of the Raf signaling pathway that are implicated in the synergistic response to LXRα activation in HCC. We will also determine the essential role of Acss2 in liver cancer and identify the cellular processes controlled by Acss2-dependent regulation of acetate metabolism. For this we will investigate the consequences of Acss2 inhibition on lipid synthesis and epigenetic regulation via histone acetylation. In addition, we will characterize the newly identified metabolic vulnerabilities in different HCC genotypes to evaluate their potential as therapeutic targets in liver cancer.