Targeting Lipid Unsaturation in Ovarian Cancer Stem Cells

靶向卵巢癌干细胞中的脂质不饱和度

• 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
• 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

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靶向卵巢的一种新的代谢易损性 我们的合作团队发现了癌症干细胞(CSC)。通过使用高光谱受激拉曼 我们鉴定的单个活细胞的散射(SRS)成像和提取的脂类的质谱分析 与非CSCs相比，卵巢CSCs中的不饱和脂肪酸(UFAs)水平升高。我们演示了 不饱和脂肪酸对卵巢CSCs的存活、增殖和致瘤性至关重要。在此，我们建议 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CSCs中的维甲酸信号，以决定细胞命运并促进 致瘤性。我们将分析饱和和不饱和脂肪之间的平衡是否会增强 化疗后耐药细胞的存活率。我们将使用SCD1击倒和化学缓蚀剂来 消除铂治疗后卵巢移植和患者来源的耐药细胞 异种移植物(PDX)。利用多通道高速SRS将在CSCs中原位显示脂质不饱和度 显微镜。无标记分子成像将对人类肿瘤中的CSCs和不饱和脂质进行量化 用铂或去饱和酶抑制剂治疗前后的异种移植物。归根结底，深入 CSCs中脂肪酸代谢的特征将揭示与茎和持久性相关的关键途径 耐受化疗的细胞。从长远来看，我们的研究将开发新的策略来攻击致命的卵巢 癌症。