Vascular regulation of fatty acid transport in metastatic tumor outgrowth

项目摘要 肿瘤转移需要微环境的支持，以促进肿瘤的生长 细胞转移性细胞从休眠状态到增殖状态的转换需要营养物质， 能量学和生物质生产。尽管肿瘤转移的代谢调控尚不完善- 建立，最近的研究表明，脂肪酸（FA）的吸收和代谢的重要性 在肿瘤细胞中驱动转移性肿瘤生长。然而，目前还不清楚FA如何在 调节肿瘤微环境。血管系统在供应 营养素本申请研究血管内皮细胞如何调节FA转运 以及在转移性肿瘤生长中的应用。我们发现Raptor/mTORC 1的缺失， 而不是Rictor/mTORC 2在血管内皮中抑制肺中的转移性肿瘤生长。 Raptor/mTORC 1缺乏导致长链脂肪酸（LCFA）和多不饱和脂肪酸减少。 内皮细胞（EC）中的PUFA，降低介导细胞凋亡的膜蛋白的表达。 FA转运，FA摄取和跨内皮转运减少，脂滴减少 转移性肿瘤基于这些初步数据，我们提出了一个模型，其中mTORC 1 血管内皮细胞的活动刺激FA的跨内皮转运，从而增强FA的跨内皮转运。 FA在肿瘤细胞和转移性生长中的利用。为了验证这一假设，我们将调查 血管mTORC 1调节脂肪酸跨膜转运的下游机制 内皮（目的1），刺激FA转运的上游因子（目的2），以及 确定选择性阻断内皮mTORC 1是否会抑制转移性生长， 改善针对转移化疗和免疫疗法（目的3）。建议的工作是创新的 在其概念中，mTORC 1调节脂肪酸肿瘤血管转运。它还 利用了几种最先进的技术，包括代谢组学筛查、MALDI成像 用于原位肿瘤切片上脂质/FA检测的质谱法，乳腺癌PDX模型， 以及几种新的条件性小鼠模型。这些研究将为今后的研究奠定基础。 开发选择性靶向内皮mTORC 1或脂肪酸转运的策略 to improve改善anti-cancer抗癌therapy疗法.

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.