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

• 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
• 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

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.

摘要 卵巢癌（OC）是最致命的妇科恶性肿瘤， 与大多数卵巢癌相关的侵袭性转移性疾病 死亡尽管OC网膜转移的临床意义， 驱动这种现象的分子机制还没有得到很好的表征， 使得所得到的攻击性表型更加令人困惑。的长期目标 这个项目是为了更全面地了解代谢因素， 这使得卵巢癌细胞能够在卵巢癌组织内的转移部位定植和增殖。 网膜我们特别感兴趣的一个方面是戊糖的作用 磷酸途径（PPP），一种负责产生核苷酸的代谢途径 戊糖前体通过一系列非氧化反应和还原反应 通过不同的氧化分支产生等价的NADPH。我们相信这条途径 有助于转移潜能和增殖。根据最近的证据 表明卵巢癌细胞经历代谢重编程以适应 独特的，富含脂质的网膜环境，我们也认为增加PPP是 通过转移细胞作为补偿机制来适应。 因此，本项目的总体目标是描述购买力平价的变化， 与网膜转移有关，在此期间，癌细胞必须适应新的 微环境生态位和迅速增殖。这个问题的核心假设是 建议是，通过以下途径产生还原当量和核苷酸前体： PPP满足增殖需求并维持所需的氧化还原稳态 大网膜转移为了确定核苷酸前体合成是否通过PPP 促进增殖，我将询问氧化分支在 目的1.体外和体内网膜转移模型。在目标2中，我将使用live-cell 网膜的活体成像与基因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。这项研究将 使我们能够推进我们对代谢景观的集体理解， 卵巢肿瘤和代谢重编程促进 转移这些见解可能会开辟治疗途径，靶向代谢 漏洞

项目成果

Using genetically encoded fluorescent biosensors to interrogate ovarian cancer metabolism.

• DOI: 10.1186/s13048-022-01046-5
• 发表时间: 2022-10-20
• 期刊: Journal of ovarian research
• 影响因子: 4