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.

项目总结

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.