Lipid programs in melanocyte transformation

黑素细胞转化中的脂质程序

基本信息

批准号：
9886716
负责人：
Richard Mark White
金额：
$ 41.08万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886716
关键词：
Acetyl Coenzyme A Adipocytes Affect Award Catecholamines Cell Culture Techniques Cell Line Cells Complement Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP DNA Sequence Alteration Data Dermal Embryo Enzymes Epigenetic Process Event Extracellular Space Fatty Acids Funding Gene Expression Genes Genetic Genetic Transcription Glucose Goals Growth Histone Acetylation Human In Vitro Interruption Invaded Knock-out Knockout Mice Lead Link Lipids Lipolysis MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Mediating Medium chain fatty acid Melanins Melanoma Cell Metabolism Modeling Nature Neural Crest Oncogenic Pharmacology Pigments Production Proliferating Proteins Role Science Signal Transduction Skin Skin Tissue Somatic Mutation Source Subcutaneous Tissue Testing Tissue Model Tissues Transgenic Organisms Translations Validation Work Zebrafish cell behavior fatty acid-transport protein histone acetyltransferase human disease human tissue in vivo long chain fatty acid melanocyte melanoma mouse model neoplastic cell non-genetic overexpression oxidation programs promoter subcutaneous therapeutic target transgene expression tumor uptake

项目摘要

The transformation of a normal melanocyte into a melanoma requires factors above and beyond genetic mutations. We have identified lipids from subcutaneous adipocytes as one such contributing factor. When nascent melanoma cells come into contact with these adipocytes, they induce lipolysis and release of fatty acids into the extracellular space. These lipids are then directly taken up into the melanoma cell through FATP1 (Fatty Acid Transport Protein 1). Using a zebrafish model of melanoma coupled with validation in human tissues, we show that genetic and pharmacologic manipulation of FAPT1 interrupts the crosstalk between adipocytes and melanoma. Once inside the melanoma cell, these fatty acids undergo β-oxidation and can fuel tumor proliferation and invasion programs. One end product of this metabolism is the production of acetyl-CoA, which we find can be used to modify histone acetylation within the melanoma cell and lead to widespread changes in gene expression. Despite the importance of the interaction between adipocytes and melanoma cells, it is unknown what signals mediate this cross-talk, or how these lipids are used by the melanoma cell to drive progression. In this proposal, we will take advantage of the complementary strengths of the zebrafish model and human cell culture models to elucidate these mechanisms. In Aim 1, we will test whether catecholamines secreted from melanoma cells, which occurs as a byproduct of melanin synthesis can induce lipolytic programs in the adipocytes. In Aim 2, we will use the rapid transgenic capabilities of the zebrafish to test whether adipocyte-specific knockout of the lipolytic enzyme ATGL abrogates melanoma growth and progression. This will be complemented using an ATGL knockout mouse melanoma model. Finally, in Aim 3 we will determine the mechanisms by which fatty acid derived acetyl-CoA modulates histone acetylation and melanoma cell behavior. These studies will highlight the way in which factors such as lipids from the microenvironment can reprogram tumor cells to enable malignant transformation. Identifying these mechanisms will provide new opportunities for therapeutic targeting of this cross-talk.

正常黑素细胞向黑色素瘤的转化需要超过基因突变的因素。我们已经将皮下脂肪细胞中的脂质确定为这样的因素。当新生的黑色素瘤细胞与这些脂肪细胞接触时，它们会诱导脂肪分解并释放到细胞外空间中。然后，通过FATP1（脂肪酸转运蛋白1）直接将这些脂质直接吸收到黑色素瘤细胞中。使用黑色素瘤的斑马鱼模型，并在人体组织中验证，我们表明，FAPT1的遗传和药物操纵会中断脂肪细胞和黑色素瘤之间的串扰。一旦进入黑色素瘤细胞，这些脂肪酸就会经历β-氧化，并可以加油肿瘤的增殖和侵袭程序。这种新陈代谢的一端产物是乙酰-COA的产生，我们发现可以用来改变黑色素瘤细胞内的组蛋白乙酰化，并导致基因表达的宽度变化。尽管脂肪细胞与黑色素瘤细胞之间的相互作用很重要，但尚不清楚哪些信号介导了这种串扰，或者黑色素瘤细胞如何使用这些脂质来驱动进展。在此提案中，我们将利用斑马鱼模型和人类细胞培养模型的完整优势来阐明这些机制。在AIM 1中，我们将测试来自黑色素细胞分泌的儿茶酚胺是否作为黑色素合成的副产品可以诱导脂肪细胞中的脂肪溶解程序。在AIM 2中，我们将使用斑马鱼的快速转基因能力来测试脂肪溶酶ATGL的脂肪细胞特异性敲除是否消除黑色素瘤的生长和进展。这将使用ATGL敲除小鼠黑色素瘤模型完成。最后，在AIM 3中，我们将确定脂肪酸衍生的乙酰-COA调节组蛋白乙酰化和黑色素瘤细胞行为的机制。这些研究将突出显示微环境中脂质等因素可以重新编程肿瘤细胞以实现恶性转化的方式。识别这些机制将为这种串扰的治疗定位提供新的机会。