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: 10680460
• 负责人: Michelle R Dawson
• 金额: $ 37.57万
• 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/10680460
• 关键词: 3-Dimensional; ATP-G-actin; Abdominal Cavity; Actins; Adipocytes; Affect; Animals; Ascites; Autophagocytosis; Autophagosome; Biological Assay; 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; Phenotype; Polymers; Primary Neoplasm; Production; Proteins; Reactive Oxygen Species; Research; Resistance; Role; Small Interfering RNA; Source; Stress; Stromal Cells; Structure; Testing; Therapeutic; Tumor Promotion; Vimentin; biophysical analysis; cancer cell; cancer therapy; cell motility; cell type; chemotherapy; fatty acid oxidation; high resolution imaging; in vivo Model; inhibition of autophagy; inhibitor; lipid metabolism; lipid transport; metabolomics; migration; neoplastic cell; new therapeutic target; novel; nutrient deprivation; paracrine; pharmacologic; polarized cell; polymerization; programs; 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.

项目摘要 上皮卵巢癌（EOC）是最致命的妇科癌。经常被诊断出来 从卵巢到网骨脂肪垫。理解和针对EOC的主要挑战是 该疾病的异质性质，这使得很难开发有效靶向和靶向的治疗方法 破坏所有癌细胞。这种异质性导致复杂的分子景观，并以 高度侵入性和化学抗性的肿瘤细胞。了解如何在癌细胞中的这种异质性是至关重要的 发展并有助于EOC疾病进展。多倍体巨癌细胞代表一个小的 耐药和休眠的癌细胞的亚群，这些癌细胞生存于治疗，后来醒来形成了新的 肿瘤细胞通过肿瘤的萌芽。肿瘤器官培养物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入性细胞如何促进EOC疾病进展。 在EOC肿瘤微环境中，癌细胞经常遇到养分的代谢应激 剥夺，缺氧和有毒疗法，可以触发代谢重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移，以满足能量需求 生存和侵入性；新陈代谢的这种转变与高能线粒体，脂质有关 液滴消失（脂解）和自噬。这在增加的PGCC中尤其重要 养分的需求部分需要它们更大的尺寸和更具侵入性的表型。另外，EOC转移形成 从从原发性肿瘤中脱落到富含脂肪细胞的腹腔的多细胞聚集体。 先前的研究表明，腹膜脂肪细胞可以将游离脂肪酸转移到EOC细胞中 为转移性肿瘤生长提供细胞能。脂肪酸为ATP依赖性提供了丰富的能源 肌动蛋白聚合和基于肌动蛋白的突起对于细胞迁移和转移过程至关重要。 我们假设侵入性EOC细胞从外源脂质来源（包括脂肪细胞和 胞质脂质液滴中富含脂质的腹水液），在代谢压力下使用这些脂质液滴生成 通过自噬迁移所需的线粒体ATP。为了证明这一假设，我们 将使用新型的3D培养模型和动物研究来跟踪单个化学抗性的代谢变化 EOC细胞以及研究脂质液滴代谢中的异质性。拟议的研究将调查 代谢和治疗应激在激活脂质代谢（AIM 1）和自噬（AIM 2）和 确定高度侵入性细胞（包括PGCC）亚群中的代谢改变如何有助于 侵袭性肿瘤的发展（AIM 3）。拟议的研究将揭示新的机制 细胞异质性和非代谢失调，以及在EOC中进行研究的新治疗靶标。

项目成果

Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations.

• DOI: 10.1038/s41598-023-46055-6
• 发表时间: 2023-11-06
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Pena, Carolina Mejia;Skipper, Thomas A.;Hsu, Jeffrey;Schechter, Ilexa;Ghosh, Deepraj;Dawson, Michelle R.
• 通讯作者: Dawson, Michelle R.

Spatial Heterogeneity in Cytoskeletal Mechanics Response to TGF-β1 and Hypoxia Mediates Partial Epithelial-to-Meshenchymal Transition in Epithelial Ovarian Cancer Cells.

• DOI: 10.3390/cancers15123186
• 发表时间: 2023-06-14
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Ghosh, Deepraj;Hsu, Jeffrey;Soriano, Kylen;Pena, Carolina Mejia;Lee, Amy H.;Dizon, Don S.;Dawson, Michelle R.
• 通讯作者: Dawson, Michelle R.