Investigating Metabolic Pathways of IL-4 that Promote Metastasis in Breast Cancer

研究促进乳腺癌转移的 IL-4 代谢途径

• 批准号: 10066537
• 负责人: Demond Williams
• 金额: $ 3.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066537
• 关键词: Affect; Attenuated; B-Lymphocytes; Behavior; Biochemical Pathway; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Breast cancer metastasis; CRISPR/Cas technology; Cancer Etiology; Carcinoma; Cells; Cessation of life; Consumption; Data; Diagnosis; Disease; Disease Progression; Early Diagnosis; Early treatment; Epigenetic Process; Genes; Glucose; Glycolysis; Goals; Histone Acetylation; Human; Image; Immune; Interleukin 4 Receptor; Interleukin-2; Interleukin-4; Knock-out; Lead; Link; Localized Disease; Lymphocyte Activation; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metastatic breast cancer; Metastatic to; Modification; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmacology; Phenotype; Positron-Emission Tomography; Property; Proto-Oncogene Proteins c-akt; Radiation therapy; Receptor Activation; Receptor Signaling; Reporting; Research; Resected; Role; Signal Transduction; Survival Rate; Testing; Woman; Work; advanced disease; cancer diagnosis; cancer imaging; cytokine; epigenetic regulation; epigenome; fatty acid oxidation; genetic manipulation; glucose metabolism; glucose uptake; improved outcome; in vivo; inhibitor/antagonist; lymphocyte proliferation; macrophage; malignant breast neoplasm; member; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; receptor expression; receptor-mediated signaling; response; targeted treatment; therapy development; traditional therapy; tumor; tumor microenvironment

Abstract Breast cancer is the most frequently diagnosed cancer among women, and the second leading cause of cancer death among women. The 5-year survival rate for breast cancer patients with localized disease is 98.7%, however with metastatic spread survival decreases to 27%. This difference in survival highlights a vital need for development of therapies targeting metastatic disease in order to improve outcomes in breast cancer patients. The Th2 cytokine interleukin-4 (IL4) has a number of established roles in immune cells. These effects include increasing glucose metabolism in B-lymphocytes, inducing fatty acid oxidation in macrophages, and regulation of epigenetic alterations that impact polarization of macrophages. The role of IL4 in cancer has largely been studied from the perspective of its effects on immune cells in the tumor microenvironment. A number of epithelial cancers, including breast cancer, express interleukin-4 receptor (IL4R). However, the effects of IL4 on IL4R expressing cancers are not as well understood as the role in immune cells. Our lab has previously demonstrated that IL4R expression in breast cancer promotes the formation of metastases, as well as enhances glucose metabolism. Our overarching idea is that IL4R mediated signaling enhances breast cancer metastasis through metabolic and epigenetic alterations, and the specific hypothesis that I will test here is that signaling through the type II IL4 receptor leads to increased glucose uptake that in turn enables enhanced histone acetylation and the manifestation of a metastatic phenotype. In order to test this hypothesis, I plan to use an unbiased mass spectrometry approach in order to characterize glucose-related metabolic alterations in breast cancer initiated by IL4 signaling. A mouse model of metastatic disease will be used to determine if IL4-dependent modification of this pathway can be detected by vivo imaging of glucose uptake. I will investigate biochemical pathways that lead to histone acetylation and ultimately relate these to metastatic properties. Pharmacological inhibition as well as CRISPR/Cas9 mediated knockout of potential downstream effectors will be used in order to understand the role of specific members of an IL4R-dependent pathway in mediating metabolic and epigenetic alterations. My research will provide some answers for two of our primary questions: 1.) What are the metabolic changes mediated by IL4R and how do they contribute to metastatic progression in breast cancer; 2.) What are the epigenetic changes induced by IL4R signaling in breast cancer and how can they contribute to metastatic progression? These results will further elucidate the mechanisms that IL4 and related cytokines exploit in order to contribute to disease progression, and bolster evidence for IL4R as a novel therapeutic target in metastatic breast cancer. In addition, by understanding the downstream signaling consequences of IL4R activation in breast cancer, we can identify other novel avenues for therapy that potentially can be developed to act synergistically with IL4R.

摘要 乳腺癌是女性中最常见的癌症，也是第二大癌症病因。 女性癌症死亡率。局部乳腺癌患者的5年生存率为 98.7%，然而随着转移扩散，存活率下降至27%。这种生存差异凸显了一个至关重要的 需要开发靶向转移性疾病的疗法，以改善乳腺癌的结局 患者Th 2细胞因子白细胞介素-4（IL 4）在免疫细胞中具有许多既定的作用。这些影响 包括增加B淋巴细胞中葡萄糖代谢，诱导巨噬细胞中脂肪酸氧化， 调节影响巨噬细胞极化的表观遗传改变。IL 4在癌症中的作用 主要从其对肿瘤微环境中免疫细胞的影响的角度进行了研究。一 许多上皮癌，包括乳腺癌，表达白细胞介素-4受体（IL 4 R）。但 IL 4对表达IL 4 R的癌症的作用不如在免疫细胞中的作用那样被充分理解。我们的实验室 先前的研究表明，乳腺癌中IL 4 R的表达也促进了转移的形成， AS增强葡萄糖代谢。我们的总体想法是，IL 4 R介导的信号转导增强乳腺癌的发生。 通过代谢和表观遗传改变的癌症转移，以及我将在这里测试的特定假设 通过II型IL 4受体的信号传导导致葡萄糖摄取增加， 增强的组蛋白乙酰化和转移表型的表现。为了验证这一假设， 我计划使用无偏质谱法来表征葡萄糖相关代谢 IL 4信号传导引发的乳腺癌改变。转移性疾病的小鼠模型将用于 确定是否可以通过葡萄糖摄取的体内成像来检测该途径的IL 4依赖性修饰。我 将研究导致组蛋白乙酰化的生化途径，并最终将这些与转移性 特性.药理学抑制以及CRISPR/Cas9介导的潜在下游基因敲除 将使用效应子以了解IL 4 R依赖性途径的特定成员在 介导代谢和表观遗传改变。我的研究将为我们的两个主要问题提供一些答案 问题：1.）IL 4 R介导的代谢变化是什么，它们如何促进转移性肿瘤的发生？ 乳腺癌的进展; 2.）乳腺癌中IL 4 R信号转导诱导的表观遗传学变化是什么 它们又是如何导致转移性进展的呢这些结果将进一步阐明其机制 IL 4和相关细胞因子利用，以促进疾病进展，并支持证据， IL 4 R作为转移性乳腺癌的新治疗靶点此外，通过了解下游 乳腺癌中IL 4 R激活的信号传导后果，我们可以确定其他新的治疗途径 可以开发出与IL 4 R协同作用的药物。