Lipid programs in melanocyte transformation

正常黑色素细胞转变为黑色素瘤需要基因突变以外的因素。我们已经确定来自皮下脂肪细胞的脂质是这样的影响因素之一。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将脂肪酸释放到细胞外空间。然后这些脂质通过 FATP1（脂肪酸转运蛋白 1）直接被黑色素瘤细胞吸收。使用黑色素瘤斑马鱼模型并在人体组织中进行验证，我们表明 FAPT1 的遗传和药理学操作可以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，这些脂肪酸就会发生β-氧化，并可以促进肿瘤增殖和侵袭程序。这种代谢的最终产物之一是乙酰辅酶A的产生，我们发现它可用于修饰黑色素瘤细胞内的组蛋白乙酰化并导致基因表达的广泛变化。尽管脂肪细胞和黑色素瘤细胞之间的相互作用很重要，但尚不清楚是什么信号介导这种相互作用，或者黑色素瘤细胞如何利用这些脂质来驱动进展。在本提案中，我们将利用斑马鱼模型和人类细胞培养模型的互补优势来阐明这些机制。在目标 1 中，我们将测试黑色素瘤细胞分泌的儿茶酚胺（黑色素合成的副产品）是否可以诱导脂肪细胞中的脂肪分解程序。在目标 2 中，我们将利用斑马鱼的快速转基因能力来测试脂肪细胞特异性敲除脂肪分解酶 ATGL 是否会消除黑色素瘤的生长和进展。这将通过 ATGL 敲除小鼠黑色素瘤模型得到补充。最后，在目标 3 中，我们将确定脂肪酸衍生的乙酰辅酶 A 调节组蛋白乙酰化和黑色素瘤细胞行为的机制。这些研究将强调微环境中的脂质等因素如何重新编程肿瘤细胞以实现恶性转化。识别这些机制将为这种串扰的治疗靶向提供新的机会。

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.