Vascular regulation of fatty acid transport in metastatic tumor outgrowth

项目概要 肿瘤转移需要支持性微环境以促进播散性肿瘤的生长 细胞。转移细胞从休眠状态转变为增殖状态需要营养物质 能源学和生物质生产。尽管肿瘤转移的代谢调控尚不完善 最近的研究证实了脂肪酸 (FA) 摄取和代谢的重要性 在驱动转移性肿瘤生长的肿瘤细胞中。然而，目前尚不清楚 FA 是如何在 肿瘤微环境受到调节。血管系统在供应血液中起着至关重要的作用 营养素。该应用研究血管内皮细胞如何调节 FA 运输 及其在转移性肿瘤生长中的利用。我们发现 Raptor/mTORC1 丢失，但是 血管内皮中的 Rictor/mTORC2 不抑制肺部转移性肿瘤的生长。 Raptor/mTORC1 缺陷导致长链脂肪酸 (LCFA) 和多不饱和脂肪减少 内皮细胞（EC）中的多不饱和脂肪酸（PUFA），介导的膜蛋白表达减少 FA 运输，减少 FA 摄取和跨内皮运输，并减少脂滴 在转移性肿瘤中。基于这些初步数据，我们提出了一个模型，其中 mTORC1 血管内皮细胞的活性刺激跨内皮 FA 转运，从而增强 FA 在肿瘤细胞和转移性生长中的利用。为了检验这个假设，我们将调查 血管 mTORC1 调节脂肪酸转运的下游机制 内皮细胞（目标 1）、刺激 FA 运输的上游因子（目标 2）以及 确定选择性阻断内皮 mTORC1 是否会抑制转移性生长，以及 改善针对转移的化疗和免疫疗法（目标 3）。拟议的工作具有创新性 mTORC1 的概念是调节脂肪酸的肿瘤血管运输。它还 采用多种最先进的技术，包括代谢组学筛选、MALDI 成像 用于肿瘤切片原位脂质/FA 检测的质谱法、乳腺癌 PDX 模型、 以及几种新的条件小鼠模型。这些研究将为未来奠定基础 开发选择性靶向内皮 mTORC1 或脂肪酸运输的策略 以改善抗癌治疗。

Project Summary Tumor metastasis requires supportive microenvironment for outgrowth of disseminated tumor cells. The switch of metastatic cells from dormant to proliferative state needs nutrients for energetics and biomass production. Although metabolic regulation of tumor metastasis is not well- established, recent studies demonstrated the importance of fatty acid (FA) uptake and metabolism in tumor cells that drives metastatic tumor outgrowth. However, it is unclear how FA pools in the tumor microenvironment is regulated. The vascular system plays a crucial role in supplying nutrients. This application investigates how vascular endothelial cells regulate FA transportation and utilization in metastatic tumor outgrowth. We discovered that loss of Raptor/mTORC1, but not Rictor/mTORC2, in vascular endothelium inhibits metastatic tumor outgrowth in lung. Raptor/mTORC1 deficiency led to reduced long chain fatty acid (LCFA) and polyunsaturated fatty acid (PUFA) in endothelial cells (EC), decreased expression of membrane proteins that mediate FA transport, reduced FA uptake and transport across endothelium, and decreased lipid droplets in metastatic tumors. Based on these preliminary data, we propose a model in which mTORC1 activities in vascular endothelial cells stimulate transendothelial FA transport, leading to enhanced FA utilization in tumor cells and metastatic outgrowth. To test this hypothesis, we will investigate downstream mechanisms by which vascular mTORC1 regulates transport of fatty acids across the endothelium (Aim 1), upper-stream factors that stimulate the FA transport (Aim 2), and determine if selectively blocking endothelial mTORC1 will suppress metastatic outgrowth and improve chemo- and immunotherapy against metastasis (Aim 3). The proposed work is innovative in its concept that mTORC1 regulates tumor blood vessel transportation of fatty acids. It also utilizes several state-of-the-art technologies, including a metabolomics screen, MALDI-imaging mass spectrometry for lipid/FA detection on tumor section in situ, a breast cancer PDX model, and several new conditional mouse models. These studies would set the stage for future development of strategies selectively targeting endothelial mTORC1 or fatty acid transportation to improve anti-cancer therapy.