Investigating the Role of Adipocyte Lipolysis in Melanoma Progression

研究脂肪细胞脂解作用在黑色素瘤进展中的作用

• 批准号: 10062908
• 负责人: Joshua M. Weiss
• 金额: $ 5.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-04 至 2022-07-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062908
• 关键词: Adipocytes; Adipose tissue; Area; Cancer Etiology; Catecholamines; Cell Communication; Cell Line; Cessation of life; Coculture Techniques; Communication; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Fatty acid glycerol esters; Fishes; Gene Transfer Techniques; Genetic; Goals; Human; Image; Investigation; Knock-out; Laboratories; Lipase; Lipids; Lipolysis; MAP Kinase Gene; Malignant Neoplasms; Mediating; Melanins; Melanoma Cell; Modeling; Mus; Neoplasm Metastasis; Nonesterified Fatty Acids; Pathway interactions; Patients; Pharmacogenetics; Pharmacology; Physiological; Pigmentation physiologic function; Play; Process; Prognostic Marker; Role; Signal Pathway; Signal Transduction; Skin Cancer; Source; System; TP53 gene; Time; Transgenic Organisms; Transplantation; Triglycerides; Visualization; Western Blotting; Xenograft procedure; Zebrafish; cancer cell; cancer initiation; cancer therapy; cellular imaging; extracellular; high resolution imaging; human disease; in vivo; in vivo Model; melanoma; member; new therapeutic target; novel strategies; novel therapeutics; overexpression; paracrine; perilipin; prevent; programs; promoter; subcutaneous; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression

PROJECT SUMMARY Melanoma is the most lethal skin cancer and there remains a need to develop new therapies for patients with disseminated disease. By identifying the communication strategies cancer depends on to survive, the tumor microenvironment (TME) can serve as a fruitful area to identify new therapeutic targets. Melanoma cells interact with adipocytes within subcutaneous fat, but the consequences of this interaction is poorly understood. Our laboratory recently discovered that melanoma cells acquire lipids from stromal adipocytes and that this leads to increased melanoma proliferation and invasion. Lipid release from adipocytes is regulated by the breakdown of triglycerides into free fatty acids, a process known as lipolysis. The ability of cancer cells to induce adipocyte lipolysis has been observed, but the mechanism by which this occurs and the consequences for cancer progression remains unclear. Our preliminary data support that melanoma cells induce adipocyte lipolysis through a secreted factor. In AIM 1, we will investigate the mechanism of melanoma-induced adipocyte lipolysis using human melanoma cell lines and adipocytes in a co-culture system. We will first identify which signaling pathways are involved and then target candidate molecules that are known to mediate lipolysis through that pathway. As a byproduct of melanin synthesis, melanoma cells secrete catecholamines, which are the primary physiologic drivers of lipolysis. Therefore, we hypothesize that melanoma cells induce adipocyte lipolysis through secreted catecholamines. We will investigate the relationship between pigmentation in melanoma and adipocyte lipolysis to understand how differentiation programs influence interactions with the TME. In AIM2, we will examine the functional consequences of adipocyte lipolysis on melanoma progression using the zebrafish as an in vivo model. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for lipolysis and has been shown to be required for cancer-induced adipocyte lipolysis. We will create an adipocyte-restricted ATGL knockout in zebrafish, which offers the advantages of rapid transgenesis and high resolution imaging of cell-cell interactions in the TME. We will use this new in vivo model to determine the role of adipocyte lipolysis in melanoma initiation and metastasis. We hypothesize that blocking adipocyte lipolysis will decrease melanoma initiation and metastasis by cutting off access to extracellular lipids and creating an unfavorable microenvironment. By investigating the role of melanoma-induced adipocyte lipolysis, this proposal seeks to understand the contribution of adipocytes to melanoma progression and identify novel approaches to target the tumor microenvironment. !

项目摘要 黑色素瘤是最致命的皮肤癌，仍然需要为患有黑色素瘤的患者开发新的疗法。 传播性疾病通过识别癌症赖以生存的沟通策略， 微环境（TME）可以作为一个富有成效的领域，以确定新的治疗靶点。黑素瘤细胞 与皮下脂肪内的脂肪细胞相互作用，但这种相互作用的后果知之甚少。 我们的实验室最近发现黑色素瘤细胞从基质脂肪细胞获得脂质， 导致黑色素瘤增殖和侵袭增加。脂肪细胞的脂质释放受 甘油三酯分解成游离脂肪酸，这一过程称为脂解。癌细胞能够 诱导脂肪细胞脂解已被观察到，但这种情况发生的机制和后果， 对癌症进展的影响尚不清楚。我们的初步数据支持黑色素瘤细胞诱导脂肪细胞 通过分泌因子进行脂肪分解。在AIM 1中，我们将研究黑色素瘤诱导的 在共培养系统中使用人黑素瘤细胞系和脂肪细胞进行脂肪细胞脂解。我们将 首先确定涉及哪些信号通路，然后靶向已知的候选分子， 通过该途径介导脂肪分解。作为黑色素合成的副产品，黑色素瘤细胞分泌 儿茶酚胺，其是脂解的主要生理驱动剂。因此，我们假设 黑色素瘤细胞通过分泌的儿茶酚胺诱导脂肪细胞脂解。我们将调查 黑色素瘤色素沉着与脂肪细胞脂解之间的关系，以了解如何分化 程序影响与TME的互动。在AIM 2中，我们将检查 使用斑马鱼作为体内模型研究脂肪细胞脂解对黑色素瘤进展的影响。脂肪 甘油三酯脂肪酶（ATGL）是脂解的限速酶，并且已被证明是 癌症诱导的脂肪细胞脂解作用。我们将在斑马鱼中建立脂肪细胞限制性ATGL敲除， 提供了TME中细胞-细胞相互作用的快速转基因和高分辨率成像的优点。我们 将使用这种新的体内模型来确定脂肪细胞脂解在黑色素瘤发生中的作用， 转移我们假设阻断脂肪细胞的脂解作用将减少黑色素瘤的发生和转移 通过切断细胞外脂质的通路并创造一个不利的微环境。通过调查 黑色素瘤诱导的脂肪细胞脂解的作用，这项建议旨在了解脂肪细胞的贡献 黑色素瘤的进展，并确定新的方法来靶向肿瘤微环境。 !