Iron, Ferroptosis and Ovarian Cancer

铁、铁死亡和卵巢癌

• 批准号: 10197796
• 负责人: Suzy V Torti
• 金额: $ 35.65万
• 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/10197796
• 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; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Predisposition; Prognosis; 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; 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 在美国，卵巢癌导致的死亡人数比任何其他妇科癌症都要多。 过去 30 年来，晚期疾病患者的情况几乎没有变化，需要新的治疗方法。 在上一个资助周期中，我们实验室发现卵巢肿瘤细胞和卵巢癌肿瘤起始 细胞（“癌症干细胞”）比其非恶性细胞获得并保留更多的铁—— 我们将这种现象称为“铁成瘾”，这种增强的铁吸收和保留促进了生长。 然而，我们发现这种增强的铁保留也会导致卵巢癌细胞。 对引发铁死亡（一种铁依赖性细胞死亡形式）的药物非常敏感。 尽管铁是铁死亡的核心，但我们对铁实际上如何赋予这种易感性知之甚少。 应用中，我们测试了这样一个假设：铁在 铁死亡，以及我们最近发现的铁死亡途径中的新靶标可能会导致 我们通过两个广泛的目标来成功干预卵巢癌：1) 更好地干预卵巢癌。 了解铁在铁死亡中的作用；2) 确定增强铁死亡活性的特定靶标。 通过在卵巢癌本身和卵巢癌中促进促铁死亡途径来诱导铁死亡 卵巢癌微环境。 我们的具体目标就是针对这些目标，在目标 1 中，我们追求铁死亡诱导剂的初步观察。 触发信号网络，促进多不饱和脂质过氧化物（近端脂质过氧化物）的产生 铁死亡的“刽子手”）。我们认为铁死亡是通过以下两种方式传播的：1）转录激活 增加不稳定铁的铁依赖性促铁死亡蛋白，以及 2) 前馈环的参与 禁用铁依赖性脂质去饱和酶 SCD1，我们最近证明该酶可以防止铁死亡。 将使用细胞培养以及卵巢癌小鼠模型来检验我们的假设。在目标 2 中，我们使用状态- 最先进的 NanoSIMS 成像和 MALDI-MSI 来探测铁死亡信号的起源位点，共同 我们利用铁死亡的典型特征——氧化脂质来定位铁，并进一步扩展了这些发现。 在目标 3 中，我们评估了卵巢肿瘤微环境中的细胞如何改变。 卵巢癌对诱导铁死亡的药物的反应我们关注巨噬细胞和成纤维细胞， 我们在试点研究中发现，与卵巢癌转移密切相关的细胞发挥着作用 旁分泌对脂质和铁代谢的影响显着影响卵巢铁死亡的程度 癌细胞。 总的来说，这些实验将增强对卵巢癌铁代谢的了解，探索调节机制 以前未与铁死亡相关的途径，并定义了肿瘤微环境对铁死亡的贡献 铁死亡——有助于在卵巢癌治疗中更有效地使用铁死亡诱导剂的努力。