Investigating the Role of Adipocyte Lipolysis in Melanoma Progression

项目总结 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治疗方法。 播散性疾病。通过确定癌症赖以生存的沟通策略，肿瘤 微环境(TME)可以作为一个富有成效的领域来寻找新的治疗靶点。黑色素瘤细胞 与皮下脂肪中的脂肪细胞相互作用，但这种相互作用的后果尚不清楚。 我们的实验室最近发现，黑色素瘤细胞从间质脂肪细胞获得类脂，这 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，这一过程称为脂肪分解。癌细胞的能力 已经观察到诱导脂肪细胞脂肪分解，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 通过一种分泌因子进行脂肪分解。在目标1中，我们将研究黑色素瘤诱导的机制 人黑色素瘤细胞系与脂肪细胞共培养体系中脂肪细胞的脂肪分解作用。我们会 首先确定哪些信号通路参与，然后针对已知的候选分子 通过这一途径来调节脂肪分解。作为黑色素合成的副产品，黑色素瘤细胞分泌 儿茶酚胺，这是脂肪分解的主要生理驱动因素。因此，我们假设 黑色素瘤细胞通过分泌儿茶酚胺诱导脂肪细胞脂解。我们将调查 黑色素瘤中色素沉着与脂肪细胞脂肪分解的关系 项目会影响与TME的互动。在AIM2中，我们将研究 以斑马鱼为活体模型研究黑色素瘤进展过程中脂肪细胞的脂解作用。脂肪 甘油三酯脂肪酶(ATGL)是脂肪分解的限速酶，已被证明是 癌症引起的脂肪细胞脂肪分解。我们将在斑马鱼中创造一个脂肪细胞受限的ATGL基因敲除，它 在TME中提供了快速转基因和细胞间相互作用的高分辨率成像的优势。我们 将使用这一新的体内模型来确定脂肪细胞脂解在黑色素瘤发生和发展中的作用 转移。我们假设阻断脂肪细胞脂解将减少黑色素瘤的发生和转移。 通过切断细胞外脂质的途径，创造一个不利的微环境。通过调查 黑色素瘤诱导脂肪细胞脂肪分解的作用，这一建议试图了解脂肪细胞的贡献 黑色素瘤的进展，并确定新的方法，以肿瘤微环境为靶点。 好了！

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. !