Metabolic rewiring regulates cancer growth and tumor-associated immune responses

项目摘要 代谢重编程被认为是癌细胞的标志，并加深了对 这些代谢变化可能导致新的和有前途的治疗方法的发展。De的激活 新的脂质合成和表观遗传重编程都是许多癌症的共同特征。乙酰辅酶A是 细胞中新合成的脂类的代谢构件。放松对脂肪合成的管制是关键 在代谢紊乱中的问题，并已被证明支持肿瘤的生长。乙酰-辅酶A也是供体 所有组蛋白和非组蛋白乙酰化的底物。我们实验室以前的研究表明，组蛋白 在体内的癌细胞和组织中，乙酰化是代谢敏感的。新陈代谢的调节如何 组蛋白乙酰化随后影响基因表达，在肿瘤发生中的信号仍然是一个领域 积极调查。癌症的另一个特征是能够逃避免疫检测或通过 各种各样的机制。识别免疫细胞在分化或分化过程中代谢重排的研究 激活已促使研究如何扰乱肿瘤内的免疫代谢以抑制抗- 肿瘤免疫。然而，癌症和免疫细胞代谢相互作用的确切机制 在肿瘤中的作用在很大程度上仍是未知的。 在本提案的博士前阶段提出的目标旨在进一步了解 细胞代谢在促进肿瘤发生中的作用。在目标1中，我研究了ACLY在调节中的作用 遗传学和药理学在细胞中的从头合成脂质和组蛋白乙酰化等过程 细胞代谢的扰动与基于质谱学的代谢组学技术及其他 生化方法。在Aim 2中，我之前的发现将在体内翻译，以调查ACLY的损失 在非酒精性脂肪肝的背景下影响肝细胞癌的发展，这种疾病有 已被确定为人类患者肝细胞癌的危险因素。我会利用饮食压力 在含有肝脏特异性Acly基因敲除的小鼠中建立致癌物诱导的肝癌模型，以研究其过程 如从头合成脂质和表观基因组重塑在此背景下受到影响。的最终目标是 这些目的是在饮食压力和肝细胞的背景下定义ACLY在细胞代谢中的功能 ACLY抑制剂在肿瘤防治中的应用 肝细胞癌。在目标3中，我建议建立在细胞和肿瘤新陈代谢的技术和概念专业知识的基础上 在我的博士后培训中获得了肿瘤免疫学和博士后奖学金 免疫新陈代谢。我描述了研究癌细胞代谢重编程的可能方法 会影响肿瘤内的免疫细胞功能。这些研究的目标是确定如何调节癌症 或免疫细胞代谢可促进抗肿瘤免疫反应，开发新的治疗策略。

Project Summary Metabolic reprogramming is recognized as a hallmark of cancer cells, and a deeper understanding of these metabolic changes can lead to the development of novel and promising therapeutics. Activation of de novo lipid synthesis and epigenetic reprogramming are both common features of many cancers. Acetyl-CoA is the metabolic building block for newly synthesized lipids in the cell. Deregulated lipid synthesis is a key problem in metabolic disorders, and has been shown to support tumor growth. Acetyl-CoA is also the donor substrate for all histone and non-histone protein acetylation. Previous studies in our lab show that histone acetylation is metabolically sensitive in cancer cell lines and tissues in vivo. How metabolic regulation of histone acetylation subsequently affects gene expression and signaling in tumorigenesis remains an area of active investigation. Another hallmark of cancer is the ability to evade immune detection or destruction through a wide variety of mechanisms. Studies identifying metabolic rewiring of immune cells during differentiation or activation have prompted research into how immunometabolism is disrupted within tumors to suppress anti- tumor immunity. However, the exact mechanisms of interplay between cancer and immune cell metabolism within a tumor remain largely unknown. The aims presented in the pre-doctoral phase of this proposal are designed to further understand the role of cellular metabolism in promoting tumorigenesis. In Aim 1, I investigate the role of ACLY in regulating processes such as de novo lipid synthesis and histone acetylation in cells using genetic and pharmacological perturbations of cellular metabolism coupled with mass-spectrometry based metabolomic techniques and other biochemical methods. In Aim 2, my previous findings will be translated in vivo to investigate how ACLY loss impacts hepatocellular carcinoma development in the context of non-alcoholic fatty liver disease, which has been identified as a risk factor for hepatocellular carcinoma in human patients. I will utilize a dietary stress and carcinogen-induced model of HCC in mice harboring a liver-specific knockout of Acly to study how processes such as de novo lipid synthesis and epigenome remodeling are impacted in this context. The ultimate goal of these aims is to define ACLY functions in cellular metabolism in the context of dietary stress and hepatocellular carcinoma for the application of ACLY inhibitors as a therapeutic strategy in the prevention and treatment of HCC. In Aim 3, I propose to build upon the technical and conceptual expertise in cellular and tumor metabolism acquired in my pre-doctoral training by pursuing a post-doctoral fellowship in tumor immunology and immunometabolism. I describe potential methods to investigate how metabolic reprogramming by cancer cells can impact immune cell function within a tumor. The goal of these studies is to identify how modulating cancer or immune cell metabolism can favor anti-tumor immune responses to develop novel therapeutic strategies.