Lipid Metabolism Switch Triggers Invasive and Chemoresistant Epithelial Ovarian Cancer Phenotype

脂质代谢开关触发侵袭性和耐药性上皮性卵巢癌表型

• 批准号: 10522428
• 负责人: Michelle R Dawson
• 金额: $ 35.32万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522428
• 关键词: 3-Dimensional; ATP-G-actin; Abdominal Cavity; Actins; Adipocytes; Affect; Animals; Ascites; Autophagocytosis; Autophagosome; Biosensor; Cell Survival; Cells; Cellular Metabolic Process; Chemoresistance; Cytosol; Data; Development; Diagnosis; Disease; Disease Progression; Drug resistance; Energy Metabolism; Energy-Generating Resources; Ensure; Environment; Epithelial ovarian cancer; Fatty Acids; Fatty acid glycerol esters; Free Energy; Genetic; Genus Hippocampus; Glycolysis; Growth; Heterogeneity; Human; Hypoxia; In Vitro; Individual; Inflammatory; Intermediate Filaments; Lipids; Lipolysis; Liquid substance; Lysosomes; Malignant Female Reproductive System Neoplasm; Measures; Mediating; Metabolic; Metabolic stress; Metabolism; Microspheres; Mitochondria; Modeling; Molecular; Mus; Nature; Neoplasm Metastasis; Nonesterified Fatty Acids; Nutrient; Omentum; Organoids; Ovary; Oxidative Phosphorylation; Pathway interactions; Peritoneal; Peritoneum; Pharmacology; Phenotype; Primary Neoplasm; Production; Proteins; Reactive Oxygen Species; Research; Resistance; Role; Small Interfering RNA; Source; Stress; Stromal Cells; Structure; Testing; Therapeutic; Vimentin; base; biophysical analysis; cancer cell; cell motility; cell type; chemotherapy; fatty acid oxidation; high resolution imaging; in vivo Model; inhibitor; lipid metabolism; lipid transport; metabolomics; migration; neoplastic cell; new therapeutic target; novel; nutrient deprivation; paracrine; polarized cell; polymerization; recruit; scaffold; single-cell RNA sequencing; three dimensional cell culture; tumor; tumor growth; tumor heterogeneity; tumor metabolism; tumor microenvironment; tumor progression

PROJECT SUMMARY Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer; frequently diagnosed after it has spread from the ovary to the omentum fat pad. A major challenge to understanding and targeting EOC is the heterogeneous nature of the disease, which makes it difficult to develop treatments that effectively target and destroy all cancer cells. This heterogeneity results in complicated molecular landscapes with subpopulations of highly invasive and chemoresistant tumor cells. It is critical to understand how this heterogeneity in cancer cells develops and contributes to EOC disease progression. Polyploidal giant cancer cells represent a small subpopulation of drug-resistant and dormant cancer cells that survive treatment and later awaken to form new tumor cells through amitotic budding. Single cell biophysical analysis of tumor organoid cultures will be used to determine how polyploidal giant cancer cells and other invasive cells contribute to EOC disease progression. In the EOC tumor microenvironment, cancer cells frequently encounter metabolic stress from nutrient deprivation, hypoxia, and toxic therapeutics, which can trigger metabolic reprogramming to promote cell survival. Cells can undergo a metabolic shift from glycolysis to oxidative phosphorylation to meet energy demands of survival and invasiveness; this shift in metabolism has been correlated with highly energetic mitochondria, lipid droplet disappearance (lipolysis), and autophagy. This is especially important in PGCCs, which have increased nutrient demands in part to their larger size and more invasive phenotype. Additionally, EOC metastases form from multicellular aggregates that are shed from the primary tumor into the adipocyte-rich abdominal cavity. Previous studies have demonstrated that peritoneal adipocytes can transfer free fatty acids to EOC cells to provide cellular energy for metastatic tumor growth. Fatty acids provide a rich energy source for ATP-dependent actin polymerization and actin-based protrusions are critical for cell migration and during metastasis. We hypothesize that invasive EOC cells store energy from exogenous lipid sources (including adipocytes and lipid-rich ascites fluid) in cytosolic lipid droplets, and under metabolic stress use these lipid droplets to generate mitochondrial ATP that is required for invasive cell migration through autophagy. To prove this hypothesis, we will use a novel 3D culture model and animal studies to track metabolic changes in individual chemoresistant EOC cells as well as study heterogeneity in lipid droplet metabolism. The proposed research will investigate the role of metabolic and treatment stress in activating lipid metabolism (Aim 1) and autophagy (Aim 2), and determine how metabolic alterations in subpopulations of highly invasive cells (including PGCCs) contribute to the development of aggressive tumors (Aim 3). The proposed studies will reveal novel mechanisms contributing to cellular heterogeneity and dysregulated metabolism, along with new therapeutic targets to investigate in EOC.

项目总结 上皮性卵巢癌(EOC)是最致命的妇科癌症，常在扩散后确诊。 从卵巢到大网膜脂肪垫。理解和瞄准EOC的一个主要挑战是 疾病的异质性，这使得很难开发有效地针对和 摧毁所有的癌细胞。这种异质性导致了复杂的分子景观，其亚群为 高度侵袭性和抗药性的肿瘤细胞。了解癌细胞中的这种异质性是如何 发展并促进EoC疾病的发展。多倍体巨型癌细胞代表着一种小的 耐药和休眠的癌细胞亚群，在治疗后存活并随后苏醒形成新的 肿瘤细胞通过无丝分裂萌发。肿瘤器官培养的单细胞生物物理分析将用于 确定多倍体巨型癌细胞和其他侵袭性细胞如何促进卵巢上皮性癌疾病的进展。 在EoC肿瘤微环境中，癌细胞经常受到营养物质的代谢应激 剥夺、缺氧和毒性治疗，可触发代谢重新编程以促进细胞存活。 细胞可以经历从糖酵解到氧化磷酸化的代谢转变，以满足以下能量需求 生存和侵袭性；这种新陈代谢的转变与高能量的线粒体、脂质有关 液滴消失(脂解)和自噬。这在PGCC中尤其重要，它们已经增加了 营养需求部分归因于它们更大的体型和更具侵袭性的表型。此外，EoC转移形成 从原发肿瘤脱落到富含脂肪细胞的腹腔的多细胞聚集体。 以前的研究表明，腹膜脂肪细胞可以将游离脂肪酸转移到EOC细胞，从而 为转移性肿瘤生长提供细胞能量。脂肪酸为三磷酸腺苷依赖提供丰富的能量来源 肌动蛋白聚合和基于肌动蛋白的突起对细胞迁移和转移至关重要。 我们假设侵袭性EOC细胞储存来自外源性脂肪来源的能量(包括脂肪细胞和 富含脂类的腹水)，在代谢压力下，利用这些脂滴生成 线粒体三磷酸腺苷是细胞通过自噬进行侵入性迁移所必需的。为了证明这一假设，我们 将使用一种新的3D培养模型和动物研究来跟踪个体化疗耐药的代谢变化 EOC细胞，以及研究脂滴代谢的异质性。拟议的研究将调查 代谢和治疗应激在激活脂代谢(目标1)和自噬(目标2)中的作用，以及 确定高侵袭性细胞亚群(包括PGCC)的代谢变化如何促进 侵袭性肿瘤的发展(目标3)。拟议中的研究将揭示新的机制 细胞异质性和代谢紊乱，以及在卵巢癌研究的新的治疗靶点。