Iron, Ferroptosis and Ovarian Cancer

铁、铁死亡和卵巢癌

• 批准号: 10429989
• 负责人: Suzy V Torti
• 金额: $ 46.94万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429989
• 关键词: Affect; Antineoplastic Agents; CREB1 gene; Cancer Etiology; Cancer Patient; Cell Culture Techniques; Cell Death; Cell Death Signaling Process; Cells; Cessation of life; Data; Epithelial ovarian cancer; Event; Exposure to; Fibroblasts; Fostering; Generations; Genes; Genetic Transcription; Goals; Grant; Growth; Homeostasis; Image; Investigation; Iron; Iron Chelating Agents; Knowledge; LCN2 gene; Laboratories; Lead; Link; Lipid Peroxidation; Lipid Peroxides; Lipids; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Names; Neoplasm Metastasis; Non-Malignant; Organelles; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Play; Predisposition; Proteins; Publishing; Regulatory Pathway; Role; Signal Pathway; Signal Transduction; Site; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stage at Diagnosis; Testing; Transcriptional Activation; Treatment Failure; Tumor-associated macrophages; addiction; advanced disease; anti-cancer; cancer cell; cancer stem cell; cancer therapy; defined contribution; desaturase; enzyme pathway; experimental study; heme oxygenase-1; improved; in vivo; innovation; insight; iron metabolism; lipid metabolism; macrophage; mouse model; neoplastic cell; novel; novel strategies; ovarian neoplasm; oxidized lipid; palliative; paracrine; patient prognosis; polyunsaturated fat; response; successful intervention; three dimensional cell culture; transcription factor; tumor; tumor microenvironment

Summary Ovarian cancer causes more deaths than any other gynecologic cancer in the US. The dismal prognosis of patients with advanced disease remains little changed in the past 30 years. New approaches are needed. In the last grant cycle, our laboratory discovered that ovarian tumor cells and ovarian cancer tumor-initiating cells (`cancer stem cells') acquire and retain substantially more iron than their non-malignant counterparts – a phenomenon we named “iron addiction”. This enhanced iron acquisition and retention facilitates growth of ovarian cancer. However, we found that this enhanced iron retention also makes ovarian cancer cells exquisitely susceptible to drugs that trigger ferroptosis, an iron-dependent form of cell death. Although iron is central to ferroptosis, little is known about how iron actually confers this susceptibility. In this application, we test the hypothesis that iron plays critical, novel, and previously undescribed roles in ferroptosis, and that new targets in the ferroptosis pathway that we recently discovered might lead to successful interventions in ovarian cancer. We approach this problem with two broad objectives: 1) to better understand the role of iron in ferroptosis; 2) to identify specific targets that will enhance the activity of ferroptosis inducers by fostering pro-ferroptotic pathways both in ovarian cancers themselves and in the ovarian cancer microenvironment. Our Specific Aims are directed at these goals. In Aim 1, we pursue pilot observations that ferroptosis inducers trigger a signaling network that fosters the generation of polyunsaturated lipid peroxides (the proximal `executioners' of ferroptosis). We propose that ferroptosis is propagated by both 1) transcriptional activation of iron-dependent pro-ferroptotic proteins that increase labile iron, and 2) engagement of a feed forward loop that disables the iron-dependent lipid desaturase SCD1 that we recently showed protects against ferroptosis. We will test our hypothesis using cell culture as well as murine models of ovarian cancer. In Aim 2, we use state- of-the-art NanoSIMS imaging and MALDI-MSI to probe the sites of origin of the ferroptotic death signal, co- localizing iron with the oxidized lipids that typify ferroptosis. We confirm and expand these findings using organelle-targeted iron chelators. In Aim 3, we assess how cells in the ovarian tumor microenvironment modify the response of ovarian cancers to drugs that induce ferroptosis. We focus on macrophages and fibroblasts, cells that are critically involved in ovarian cancer metastasis, which we discovered in pilot studies exert paracrine effects on lipid and iron metabolism that dramatically affect the degree of ferroptosis in ovarian cancer cells. Collectively, these experiments will enhance knowledge of ovarian cancer iron metabolism, explore regulatory pathways not previously linked to ferroptosis, and define the contribution of the tumor microenvironment to ferroptosis - efforts that will help to direct more effective use of ferroptosis inducers in ovarian cancer therapy.

概括 卵巢癌导致与美国任何其他妇科癌症相比，导致死亡更多。令人沮丧的进展 在过去的30年中，患有晚期疾病的患者几乎没有改变。需要新的方法。 在上一个赠款周期中，我们的实验室发现卵巢肿瘤细胞和卵巢癌肿瘤发射 细胞（“癌症干细胞”）获得并保留的铁比非机场的铁 - A 现象我们命名为“铁成瘾”。这种增强的铁采集和保留促进了 卵巢癌。但是，我们发现这种增强的铁保留也使卵巢癌细胞 非常容易受到触发铁铁作用的药物，这是一种依赖于细胞死亡的铁的形式。 尽管铁对铁肉芽生殖是核心，但对铁实际承认这种敏感性的认识鲜为人知。在这个 应用，我们检验了铁在 铁凋亡，以及我们最近发现的铁铁作用途径中的新靶标可能会导致 成功干预卵巢癌。我们用两个广泛的对象解决这个问题：1） 了解铁在铁铁作用中的作用； 2）确定将增强活动的特定目标 通过在卵巢癌本身和 卵巢癌微环境。 我们的具体目标是针对这些目标的。在AIM 1中，我们追求飞行员影响者的试点观察 触发一个信号网络，该信号网络促进了多不饱和脂质过氧化物的产生（近端 铁肉芽症的“执行者”）。我们建议通过两者传播铁铁作用1） 铁依赖性的促铁蛋白会增加不稳定的铁，2）饲料前循环的参与度 禁用我们最近显示的预防性铁毒性的铁依赖性脂质去饱和酶SCD1。我们 将使用细胞培养以及卵巢癌的鼠模型检验我们的假设。在AIM 2中，我们使用状态 - Art nanosims成像和MALDI-MSI，以探测铁毒性死亡信号的起源部位，共同 用氧化的脂质来定位铁，这些脂质的特征是铁铁的。我们使用 靶向器官的铁螯合剂。在AIM 3中，我们评估卵巢肿瘤微环境中的细胞如何修饰 卵巢癌对诱导铁铁作用的药物的反应。我们专注于巨噬细胞和成纤维细胞， 与卵巢癌转移相关的细胞，我们在试点研究中发现了这些细胞 旁分泌对脂质和铁代谢的作用极大地影响了卵巢的铁凋亡程度 癌细胞。 总的来说，这些实验将增强对卵巢癌铁代谢的知识，探索调节性 以前与铁吞作用相关的途径，并定义了肿瘤微环境对 铁凋亡 - 努力将有助于指导在卵巢癌疗法中更有效地使用促进性铁氧作用。