Metabolic rewiring regulates cancer growth and tumor-associated immune responses

代谢重组调节癌症生长和肿瘤相关免疫反应

基本信息

批准号：
10556436
负责人：
Steven Zhao
金额：
$ 9.31万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2023-05-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10556436
关键词：
ATP Citrate (pro-S)-Lyase Acetates Acetyl Coenzyme A Affect Area Biochemical Biological Response Modifiers Cancer cell line Cancerous Carcinogens Cardiovascular Diseases Cell model Cell physiology Cells Cellular Metabolic Process Cessation of life Characteristics Clinical Trials Compensation Coupled Detection Development Diabetes Mellitus Diet Disease Dyslipidemias Enzymes Epigenetic Process Fellowship Gene Expression Genetic Glucose Goals Growth Hepatic Hepatocyte Histone Acetylation Histones Human Immune Immune Evasion Immune response Immune signaling Immune system Immunology Immunosuppression Impairment Incidence Investigation Knock-out Knockout Mice Knowledge Link Lipids Liver Liver Dysfunction Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolic syndrome Metabolism Methods Molecular Mus Nutrient Pathogenesis Patient-Focused Outcomes Patients Phase Play Postdoctoral Fellow Prevention Primary carcinoma of the liver cells Process Prognosis Proliferating Protein Acetylation RNA Interference Regulation Research Risk Factors Role Signal Transduction Source Stress Survival Rate Techniques Testing Therapeutic Tissues Training Translating Tumor Immunity Tumor-infiltrating immune cells United States anti-tumor immune response cancer cell chemical carcinogen design dietary epigenome hypercholesterolemia improved in vivo inhibitor interest lipid biosynthesis liver cancer model metabolomics mouse model non-alcoholic fatty liver disease non-histone protein novel novel therapeutic intervention novel therapeutics pharmacologic post-doctoral training pre-doctoral prevent therapeutic target tumor tumor growth tumor immunology tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

项目摘要代谢重编程被认为是癌细胞的标志，对这些代谢变化可以导致新颖和有前途的治疗学的发展。 DE的激活 Novo脂质合成和表观遗传重编程都是许多癌症的常见特征。乙酰辅酶A是细胞中新合成的脂质的代谢构件。放松管制的脂质合成是关键代谢性疾病的问题，已被证明支持肿瘤生长。乙酰辅酶A也是供体所有组蛋白和非历史蛋白乙酰化的底物。我们实验室的先前研究表明组蛋白乙酰化在癌细胞系和体内组织中具有代谢敏感。如何代谢调节组蛋白乙酰化随后影响肿瘤发生的基因表达和信号传导仍然是积极调查。癌症的另一个标志是能够通过多种机制。在分化或激活促使研究如何在肿瘤中破坏免疫代谢以抑制抗抗菌肿瘤免疫。但是，癌症与免疫细胞代谢之间相互作用的确切机制在肿瘤内仍然很少知道。本提案的博士前阶段中提出的目的旨在进一步了解细胞代谢在促进肿瘤发生中的作用。在AIM 1中，我研究了ACLY在调节中的作用使用遗传学和药理的过程，例如从头脂质合成和细胞中组蛋白乙酰化等过程细胞代谢的扰动以及基于质谱的代谢组技术和其他生化方法。在AIM 2中，我以前的发现将在Vivo中翻译，以调查Acly损失在非酒精性脂肪肝病的背景下影响肝细胞癌发育被确定为人类患者肝细胞癌的危险因素。我会利用饮食压力具有肝脏特异性敲除Acly的小鼠中的致癌模型，以研究过程如何在这种情况下，例如从头脂质合成和表观基因组的重塑受到影响。最终目标这些目的是在饮食胁迫和肝细胞的背景下定义细胞代谢中的ACLY功能癌用于在预防和治疗中应用ACLY抑制剂作为治疗策略 HCC。在AIM 3中，我建议建立在细胞和肿瘤代谢方面的技术和概念专业知识的基础上通过追求肿瘤免疫学和博士后研究金和免疫代谢。我描述了研究癌细胞代谢重编程的潜在方法会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有利于抗肿瘤免疫反应来发展新的治疗策略。