Investigating the Metabolic Reprogramming of Ovarian Tumors During Omental Metastasis

研究卵巢肿瘤大网膜转移期间的代谢重编程

基本信息

批准号：
10328248
负责人：
Shree Bose
金额：
$ 3.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328248
关键词：
Abdominal Cavity Adipocytes Adjuvant Affect Biological Assay Biosensor Cancer cell line Cell Proliferation Cell Survival Cells Cessation of life Characteristics Chicago Coculture Techniques Collaborations Coupled Databases Diagnosis Disease Environment Fatty acid glycerol esters Generations Goals Hematogenous Homeostasis Hydrogen Peroxide Implant In Vitro Knock-out Lipids Liquid Chromatography Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant neoplasm of ovary Mass Spectrum Analysis Metabolic Metabolic Pathway Metastatic to Modeling Molecular NADP Neoplasm Metastasis Nonesterified Fatty Acids Nucleotides Obesity Omentum Operative Surgical Procedures Outcome Study Ovarian Oxidation-Reduction Oxidative Stress Pathway interactions Patient-Focused Outcomes Patients Pentosephosphate Pathway Pentoses Peritoneum Pharmacology Phenotype Platinum Play Primary Neoplasm Production Proliferating Public Health Reaction Recurrence Research Resolution Role Sampling Series Site Solid Neoplasm Survival Rate System Testing Therapeutic Tissues Treatment Protocols Tropism Universities Up-Regulation Western Blotting Work Xenograft procedure base cancer cell chemotherapy clinically significant cohort dietary enzyme activity enzyme pathway epidemiology study improved in vivo in vivo Model insight interest intravital imaging live cell imaging meetings metabolomics nucleotide metabolism ovarian neoplasm ratiometric sensor taxane therapeutically effective transcriptomics

项目摘要

ABSTRACT Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of ovarian cancer related deaths. Despite the clinical significance of OC omental metastases, the precise molecular mechanisms which drive this phenomenon have not been well characterized, making the resulting aggressive phenotype even more puzzling. The long-term goal of this project is develop a more comprehensive understanding of the metabolic factors which allow ovarian cancer cells to colonize and proliferate at metastatic sites within the omentum. One aspect we are particularly interested in is the role of the pentose phosphate pathway (PPP), a metabolic pathway responsible for producing nucleotide pentose precursors through a nonoxidative series of reactions and the reducing equivalent NADPH through a distinct oxidative branch. We believe this pathway may contribute to metastatic potential and proliferation. Building on recent evidence demonstrating that ovarian cancer cells undergo metabolic reprogramming to adapt to the unique, lipid rich omentum environment, we also believe that increased PPP is adapted by metastasizing cells as a compensatory mechanism. Thus the overall aim of this project is characterize changes in the PPP which are relevant for omental metastases, during which cancer cells must both adjust to a new microenvironmental niche and proliferate rapidly. The central hypothesis of this proposal is that the generation of reducing equivalents and nucleotide precursors via the PPP meets the proliferative demands and maintains the redox homeostasis required for omental metastasis. To determine if nucleotide precursor synthesis via the PPP promotes proliferation, I will interrogate the importance the oxidative branch using in vitro and in vivo models on omental metastasis in Aim 1. In Aim 2, I will use live-cell intravital imaging of the omentum coupled with genetically-expressed biosensors to define the redox requirements of metastatic colonization. This proposed research will allow us to advance our collective understanding of the metabolic landscape present in ovarian tumors and the precise manner in which metabolic reprogramming promotes metastasis. These insights may open therapeutic avenues to target metabolic vulnerabilities.

抽象的卵巢癌（OC）是最致命的妇科恶性肿瘤，有侵略性转移性疾病，导致大多数卵巢癌与死亡人数。尽管OC迁移转移具有临床意义，但精确驱动这种现象的分子机制尚未得到很好的特征， making the resulting aggressive phenotype even more puzzling.长期目标该项目对代谢因素有了更全面的了解这使卵巢癌细胞在转移部位定植和增殖 omentum。我们特别感兴趣的一个方面是五旬节的角色磷酸盐途径（PPP），这是一种负责产生核苷酸的代谢途径通过非氧化反应和还原的戊糖前体。通过明显的氧化分支等效纳德。我们相信这条路可能有助于转移潜力和增殖。以最新证据为基础证明卵巢癌细胞进行代谢重编程以适应独特的，富含脂质的大脑环境，我们还认为PPP的增加是通过转移细胞作为补偿机制进行调整。因此，该项目的总体目的是表征PPP的变化与遗传转移相关，在此期间，癌细胞都必须调整为新的微环境利基市场迅速增殖。中心假设 proposal is that the generation of reducing equivalents and nucleotide precursors via PPP满足了增生的要求，并保持了所需的氧化还原稳态对于肿瘤转移。确定核苷酸前体是否通过PPP合成促进增殖，我将使用IN询问氧化分支的重要性 AIM 1中的体外和体内模型。在AIM 2中，我将使用活细胞大脑的静脉成像与遗传表达的生物传感器相结合定义转移性定植的氧化还原要求。这项拟议的研究将允许我们提高我们对存在的代谢景观的集体理解卵巢肿瘤和代谢重编程促进的精确方式转移。这些见解可能会开放靶向代谢的治疗途径漏洞。