Targeting lipid synthesis and NADPH regeneration in cancer

肝脏脂肪生成是一种基本的细胞过程，它允许脂肪酸从头合成以储存能量、膜生物合成和产生信号分子。我们现在可以证明，由肝脏X受体α(LXRα)激活触发的增强脂肪生成是一种潜在的抗肝癌新治疗策略。在小鼠肝癌模型以及人和小鼠肝癌细胞中的治疗研究表明，LXRα的药理刺激与同时阻断Raf激酶相结合，可导致肝癌细胞脂质堆积和死亡，并延长荷瘤小鼠的生存时间。我们观察到，小鼠对LXRα的激活总体上耐受性良好，这表明治疗窗口使这种治疗方法的可行性成为可能。有趣的是，我们发现Raf抑制剂和肝癌药物索拉非尼是一种适度的LXRα激活剂，并可能表明增强LXRα信号有助于其疗效。然而，用已建立的药理LxRα激动剂治疗完全激活LxRα可显著改善索拉非尼在肝癌中的治疗效果。我们还获得证据表明，抑制脂质合成可能是癌症治疗的有效策略。我们可以证明，携带不同致癌驱动因子(NRAS、Akt)的肝癌细胞表现出特定的代谢表型，Akt驱动的肝癌细胞选择性地依赖于乙酸酯来合成乙酰辅酶A。抑制乙酰辅酶A合成酶2(Acss2)是催化该反应的酶，改变了醋酸酯代谢和组蛋白乙酰化，并降低了Akt驱动的肝癌细胞的存活率。此外，我们已经进行了功能基因筛选，以确定肝癌中可能代表新的治疗靶点的额外代谢易损性。在这项建议中，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造脂途径的药理和遗传操作的影响。我们想要描述α诱导肝癌细胞应激反应的特征，并阐明确定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LXRα激活的协同反应有关的那些成分。我们还将确定Acss 2在肝癌中的重要作用，并确定Acss 2依赖的醋酸盐代谢调节所控制的细胞过程。为此，我们将研究通过组蛋白乙酰化抑制Acss2对脂质合成和表观遗传调节的影响。此外，我们还将对新发现的不同肝癌基因型的代谢易损性进行表征，以评估它们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.