Targeting Lipid Unsaturation in Ovarian Cancer Stem Cells

靶向卵巢癌干细胞中的脂质不饱和度

基本信息

批准号：
10411394
负责人：
Ji-Xin Cheng
金额：
$ 11.64万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411394
关键词：
Aftercare Animal Model Area Biology Cancer Model Cell Line Cells Characteristics Chemicals Clinical Data Development Drug Tolerance Equilibrium Fatty Acid Desaturases Fatty Acids Human Image In Situ Label Link Lipids Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Microscope Modeling Monitor Monounsaturated Fatty Acids Nuclear Oncogenic Outcome Ovarian Pathway interactions Platinum Polyunsaturated Fatty Acids Population Primary Neoplasm Publishing Recurrence Relapse Reporting Residual state Resistance Resources Retinoids Signal Transduction Small Interfering RNA Speed Stearoyl-CoA Desaturase Stem Cell Development Technology Testing Therapeutic Time Tretinoin Tumor Debulking Tumor Tissue Tumorigenicity Unsaturated Fats Unsaturated Fatty Acids Visualization Work Xenograft procedure aldehyde dehydrogenases base cancer stem cell chemotherapy desaturase fatty acid metabolism imaging platform in vivo inhibitor/antagonist innovation knock-down lipid biosynthesis lipid metabolism metabolomics molecular imaging multimodality new technology novel novel strategies patient derived xenograft model prevent response saturated fat self-renewal small molecule inhibitor spectroscopic imaging stearoyl-coenzyme A stem cell biomarkers stem cell proliferation stem cells stemness targeted treatment tool transcriptome sequencing tumor tumor initiation tumor microenvironment tumor xenograft

项目摘要

The focus of this multi-PI R01 application is to characterize and target a new metabolic vulnerability of ovarian cancer stem cells (CSCs) discovered by our collaborative team. By using hyperspectral-stimulated Raman scattering (SRS) imaging of single living cells and mass spectrometry analysis of extracted lipids we identified increased levels of unsaturated fatty acids (UFAs) in ovarian CSCs compared to non-CSCs. We demonstrated that UFAs are critical to the survival, proliferation, and tumorigenicity of ovarian CSCs. Here we propose to analyze the mechanisms by which increased lipid unsaturation mediated by Δ9 desaturase (stearoyl-coA desaturase, SCD1) regulates retinoic acid signaling in ovarian CSCs to determine cellular fate and promote tumorigenicity. We will analyze whether the balance between saturated and unsaturated lipids enhance the survival of drug-tolerant cells after chemotherapy. We will use SCD1 knock down and chemical inhibitors to eradicate drug-tolerant cells persisting after treatment with platinum in ovarian xenografts and patient derived xenografts (PDX). Lipid unsaturation will be visualized in CSCs in situ by using a multimodal high-speed SRS microscope. Label-free molecular imaging will quantify CSCs and unsaturated lipids in human tumors and xenografts before and after treatment with platinum or desaturase inhibitors. Ultimately, in depth characterization of fatty acid metabolism in CSCs will reveal key pathways linked to stemness and persistence of chemotherapy-tolerant cells. In the long run, our studies will develop new strategies to attack deadly ovarian cancer.

这种多 PI R01 应用的重点是表征和针对卵巢的新代谢脆弱性我们的合作团队使用高光谱刺激拉曼发现了癌症干细胞 (CSC)。单个活细胞的散射（SRS）成像和我们鉴定的提取脂质的质谱分析我们证明，与非 CSC 相比，卵巢 CSC 中的不饱和脂肪酸 (UFA) 水平有所增加。 UFA 对卵巢 CSC 的存活、增殖和致瘤性至关重要。分析 Δ9 去饱和酶（硬脂酰辅酶 A）介导的脂质不饱和度增加的机制去饱和酶，SCD1）调节卵巢 CSC 中的视黄酸信号传导，以确定细胞命运并促进我们将分析饱和和不饱和脂质之间的平衡是否增强了致瘤性。我们将使用 SCD1 敲除和化学抑制剂来抑制化疗后耐药细胞的存活。根除卵巢异种移植物和患者来源的铂治疗后持续存在的耐药细胞异种移植物 (PDX) 将通过使用多模式高速 SRS 在原位可视化 CSC。无标记分子成像将量化人类肿瘤中的 CSC 和不饱和脂质。最终，深入研究用铂或去饱和酶抑制剂治疗前后的异种移植物。 CSC 中脂肪酸代谢的表征将揭示与干性和持久性相关的关键途径从长远来看，我们的研究将开发攻击致命卵巢的新策略。癌症。