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，更深入地了解 这些代谢变化可导致新的和有希望的治疗剂的开发。激活de 新脂质合成和表观遗传重编程是许多癌症的共同特征。乙酰辅酶a 细胞中新合成脂质的代谢基础。脂质合成失调是 代谢紊乱的问题，并已被证明支持肿瘤生长。乙酰辅酶A也是 所有组蛋白和非组蛋白乙酰化底物。我们实验室以前的研究表明， 乙酰化在体内癌细胞系和组织中是代谢敏感的。代谢调节是如何 组蛋白乙酰化随后影响肿瘤发生中的基因表达和信号传导仍然是研究的一个领域。 积极调查。癌症的另一个标志是通过免疫系统逃避免疫检测或破坏的能力。 各种各样的机制研究确定免疫细胞在分化过程中的代谢重新布线， 激活的研究促使人们研究肿瘤内的免疫代谢是如何被破坏以抑制抗- 肿瘤免疫然而，癌症和免疫细胞代谢之间相互作用的确切机制 在肿瘤中的作用仍然是未知的。 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。在目的1中，我研究了ACLY在调节 利用遗传学和药理学方法在细胞中进行诸如从头脂质合成和组蛋白乙酰化的过程 细胞代谢的扰动与基于质谱的代谢组学技术和其他 生物化学方法在目标2中，我以前的研究结果将在体内转化，以研究ACLY丢失如何影响动物的健康。 在非酒精性脂肪肝的背景下影响肝细胞癌的发展， 已被确定为人类患者肝细胞癌的危险因素。我将利用饮食压力， 致癌物诱导的肝癌模型，小鼠携带肝脏特异性敲除Acly，以研究如何处理 例如从头脂质合成和表观基因组重塑在这种情况下受到影响。的最终目标 这些目的是在饮食应激和肝细胞损伤的背景下， ACLY抑制剂作为预防和治疗癌症的治疗策略的应用 HCC。在目标3中，我建议建立在细胞和肿瘤代谢的技术和概念专业知识的基础上 在我的博士前培训中获得了肿瘤免疫学博士后奖学金， 免疫代谢我描述了潜在的方法来调查如何代谢重编程癌细胞 可以影响肿瘤内的免疫细胞功能。这些研究的目的是确定如何调节癌症 或免疫细胞代谢可以促进抗肿瘤免疫应答，以开发新的治疗策略。

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.