Characterization of Altered Fatty Acid Trafficking in Triple-Negative Breast Cancer

三阴性乳腺癌中脂肪酸运输改变的特征

• 批准号: 10734556
• 负责人: Jeremy Williams
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-03 至 2024-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10734556
• 关键词: Apoptosis; Attenuated; Autophagocytosis; Binding; Biochemistry and Cellular Biology; Bioenergetics; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; CRISPR/Cas technology; Cancer Etiology; Carbon; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Clinical; Clinical Treatment; Cultured Tumor Cells; Data; Defect; Diagnosis; ERBB2 gene; Estrogen Antagonists; Ethics; Fatty Acids; Genetic; Glucose; Glutamine; Goals; Growth; Homeostasis; Immunocompetent; Impairment; In Vitro; Intervention; Investigation; Label; Ligands; Lipids; MYC gene; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mus; Normal Cell; Oncogenes; Oxygen Consumption; Pathway interactions; Patients; Play; Primary Neoplasm; Proliferating; Proliferation Marker; Proto-Oncogenes; Regulation; Role; Sampling; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Cell Line; United States; Up-Regulation; Visualization; Woman; Xenograft procedure; aggressive breast cancer; c-myc Genes; cancer diagnosis; cancer subtypes; cancer type; carcinogenesis; endoplasmic reticulum stress; experimental study; fatty acid metabolism; fatty acid oxidation; fatty acid-binding proteins; glucose metabolism; in vivo; insight; knock-down; lipid metabolism; malignant breast neoplasm; metabolomics; mortality; mouse model; new therapeutic target; novel; overexpression; oxidation; parent grant; pharmacologic; receptor; small molecule; therapeutic target; trafficking; triple-negative invasive breast carcinoma; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ABSTRACT – NO CHANGES FROM PARENT GRANT F31CA243468 Breast cancer is the most diagnosed cancer type and the second leading cause of cancer-related death in women in the United States. For the receptor positive (RP) subtype comprising the majority of diagnoses, clinical interventions have been largely effective in limiting associated mortality when compared with other cancers. However, the remaining 20%, which comprise the triple-negative breast cancer (TNBC) subtype, lack known therapeutic targets and are the most clinically challenging. Cancers display altered metabolism upon carcinogenesis. However, the efficacy of targeting metabolism in cancer depends upon understanding metabolic dysregulation in the context of a specific oncogene. Our lab and others have shown that levels of c-MYC (MYC), a proto-oncogene that dynamically regulates numerous cellular functions during transformation, are increased in a majority of TNBC. MYC is known to regulate glucose and glutamine metabolism in cancer, but our lab has shown that MYC regulates another important bioenergetic pathway, fatty acid oxidation (FAO), in TNBC. Models for MYC-overexpressing TNBC display decreased bioenergetic metabolism and primary tumor growth upon inhibition of FAO, indicating novel reliance on that pathway. Here, we propose to investigate how TNBC permit increased FAO. Increased FAO necessitates alterations to fatty acid (FA) availability, and one fatty acid trafficking component, fatty acid binding protein 5 (FABP5), is upregulated in TNBC in a MYC-dependent manner. FABPs are lipid chaperones that bind cytosolic FA and other molecules, and can access a range of cellular compartments. Our data indicate that FABP5 loss in MO-TNBC is sufficient to cause defects in cell metabolism and proliferation. FABP5 may contribute to altered FAO and proliferation by facilitating increased FA supply at the mitochondria to permit increased oxidation. We hypothesize that increased trafficking of FA to the mitochondria by FABP5 facilitates altered FAO in a MYC-dependent manner. Accordingly, we propose investigation of the cellular biology and biochemistry of FA trafficking, FABP5 regulation and FAO in TNBC. Our strategy combines: utilization of high-content microscopy to visualize FA trafficking in vitro, carbon-tracing studies to follow FA metabolism in vivo and in vitro, mass spectrometry-based metabolomic analyses, pharmacological and genetic perturbations of FA trafficking, and conditional and constitutive MO-TNBC cell lines and tumor models. We expect that our investigation of mechanisms of FAO in MO-TNBC will advance understanding of how FA metabolism is regulated in cancer, and may identify novel therapeutic targets for the treatment of this clinically challenging breast cancer subtype.

项目摘要/摘要 – 母基金 F31CA243468 没有变化 乳腺癌是诊断最多的癌症类型，也是癌症相关死亡的第二大原因 美国的女性。对于占大多数诊断的受体阳性（RP）亚型， 与其他方法相比，临床干预措施在很大程度上有效地限制了相关死亡率 癌症。然而，剩下的 20%，即三阴性乳腺癌 (TNBC) 亚型，缺乏 已知的治疗靶点，并且是最具临床挑战性的。 癌症在癌变时表现出代谢改变。然而，靶向代谢的功效 癌症取决于对特定癌基因背景下代谢失调的理解。我们的实验室 等人已经表明，c-MYC (MYC) 的水平是一种原癌基因，可动态调节许多 大多数 TNBC 中细胞功能在转化过程中得到增强。众所周知，MYC 可以调节 癌症中的葡萄糖和谷氨酰胺代谢，但我们的实验室已经表明 MYC 调节另一个重要的代谢 TNBC 中的生物能途径，脂肪酸氧化 (FAO)。 MYC 过度表达 TNBC 显示模型 抑制FAO后生物能代谢和原发性肿瘤生长减少，表明新的依赖性 在那条路上。在这里，我们建议调查TNBC 如何允许增加FAO。 粮农组织的增加需要改变脂肪酸（FA）的供应，以及脂肪酸贩运的一个组成部分， 脂肪酸结合蛋白 5 (FABP5) 在 TNBC 中以 MYC 依赖性方式上调。 FABP 是脂质 结合胞质 FA 和其他分子的分子伴侣，可以进入一系列细胞区室。我们的 数据表明，MO-TNBC 中 FABP5 的缺失足以导致细胞代谢和增殖缺陷。 FABP5 可能通过促进线粒体 FA 供应的增加来改变 FAO 和增殖 以允许增加氧化。我们假设 FABP5 增加了 FA 向线粒体的运输 促进以 MYC 依赖的方式改变粮农组织。因此，我们建议对细胞的研究 TNBC 中 FA 贩运的生物学和生物化学、FABP5 调控和FAO。我们的策略结合了： 利用高内涵显微镜观察 FA 体外运输情况，跟踪 FA 的碳追踪研究 体内和体外代谢、基于质谱的代谢组学分析、药理学和遗传学 FA 运输的扰动，以及条件性和组成性 MO-TNBC 细胞系和肿瘤模型。 我们期望我们对 MO-TNBC 中FAO机制的调查将加深对FA如何运作的理解 代谢在癌症中受到调节，并且可以在临床上确定治疗这种疾病的新治疗靶点 具有挑战性的乳腺癌亚型。