Vascular regulation of fatty acid transport in metastatic tumor outgrowth

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.