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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要上皮性卵巢癌（EOC）是最致命的妇科癌症；经常在传播后被诊断出来从卵巢到大网膜脂肪垫。理解和瞄准 EOC 的一个主要挑战是该疾病的异质性，这使得开发有效靶向和治疗的方法变得困难消灭所有癌细胞。这种异质性导致复杂的分子景观与亚群高度侵袭性和化学耐药性的肿瘤细胞。了解癌细胞中的这种异质性是如何产生的至关重要发展并促进 EOC 疾病进展。多倍体巨型癌细胞代表了一个小的耐药和休眠癌细胞亚群，它们在治疗中存活下来，随后苏醒形成新的癌细胞肿瘤细胞通过无丝分裂出芽。肿瘤类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袭性细胞如何促进 EOC 疾病进展。在 EOC 肿瘤微环境中，癌细胞经常遇到来自营养物质的代谢应激剥夺、缺氧和有毒治疗，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变，以满足能量需求生存和入侵；这种新陈代谢的转变与高能量线粒体、脂质液滴消失（脂肪分解）和自噬。这对于 PGCC 来说尤其重要，因为 PGCC 已经增加了营养需求的部分原因是它们体型较大，表型更具侵入性。此外，EOC 转移形成来自原发肿瘤脱落到富含脂肪细胞的腹腔中的多细胞聚集体。先前的研究表明，腹膜脂肪细胞可以将游离脂肪酸转移至EOC细胞，以为转移性肿瘤的生长提供细胞能量。脂肪酸为 ATP 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于细胞迁移和转移过程至关重要。我们假设侵入性 EOC 细胞储存来自外源脂质来源（包括脂肪细胞和脂肪细胞）的能量。富含脂质的腹水）存在于细胞质脂滴中，并且在代谢应激下利用这些脂滴产生通过自噬进行侵袭性细胞迁移所需的线粒体 ATP。为了证明这个假设，我们将使用新颖的 3D 培养模型和动物研究来追踪个体化疗耐药性的代谢变化 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质代谢（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）的代谢改变如何促进侵袭性肿瘤的发展（目标 3）。拟议的研究将揭示有助于细胞异质性和代谢失调，以及 EOC 中需要研究的新治疗靶点。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations.

比较化疗难治性和化疗耐药性卵巢癌细胞群的分泌组。

DOI：
发表时间：
2022-03-10
期刊：
影响因子：
5.2
作者：
Lee, Amy H;Mejia Peña, Carolina;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.

细胞骨架力学对 TGF-β1 和缺氧反应的空间异质性介导上皮性卵巢癌细胞的部分上皮到间质的转变。

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

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

节拍和单次高剂量紫杉醇治疗会产生不同的异质化疗耐药癌细胞群。

DOI：
发表时间：
2023-11-06
期刊：
影响因子：
4.6
作者：
Mejia Peña, Carolina;Skipper, Thomas A;Hsu, Jeffrey;Schechter, Ilexa;Ghosh, Deepraj;Dawson, Michelle R
通讯作者：
Dawson, Michelle R