Lipid storage and catabolism as drivers of metastatic invasion

脂质储存和分解代谢是转移侵袭的驱动因素

• 批准号: 10735785
• 负责人: Gina Lynn Razidlo
• 金额: $ 36.92万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735785
• 关键词: Acute; Automobile Driving; Biochemical; Biochemistry; Cancer Etiology; Catabolism; Cell Respiration; Cells; Cellular biology; Cessation of life; Circulation; Data; Dependence; Disease Progression; Down-Regulation; Energy-Generating Resources; Environment; Enzymes; Epigenetic Process; Fatty Acids; Goals; In Vitro; Invaded; KRAS oncogenesis; KRAS2 gene; Lead; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Microtubules; Mitochondria; Molecular; Mutate; Mutation; Neoplasm Metastasis; Obesity; Oncogenes; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Process; Quantitative Microscopy; Regulation; Research; Respiration; Risk Factors; Role; Signal Transduction; Source; Stimulus; Testing; Therapeutic; Transcriptional Regulation; Tumor Cell Invasion; Tumor Cell Migration; Tumor Promotion; cancer cell; cancer survival; cancer therapy; cell motility; experimental study; fatty acid oxidation; improved; in vivo; in vivo Model; insight; lipid metabolism; live cell imaging; migration; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; pancreatic cancer cells; pancreatic cancer model; programs; spatial integration; sterol esterase; targeted treatment; therapeutic target; trafficking; tumor growth; tumor metabolism; tumor progression; uptake; virtual

Metastasis is the primary cause of cancer death, yet therapeutic strategies to inhibit metastatic invasion do not exist. The long-term goal of our research program is to define the molecular mechanisms driving metastatic invasion, with the goal of identifying novel therapeutic targets and strategies to improve cancer survival. While tumor cells are known to undergo metabolic reprogramming to support tumor growth, the metabolic drivers of metastasis are poorly understood. This proposed research will define how stored lipids are used as a fuel source to power metastatic invasion in pancreatic cancer. We have preliminary data that pancreatic tumor cells undergo a shift towards lipid storage, and that this is required for invasion. This occurs through a suppression of the hormone sensitive lipase (HSL) by the oncogene KRAS, leading to lipid accumulation and priming tumor cells for metastasis. These stored lipid droplets are then catabolized during the process of invasion via the action of lipases. This results in increased oxidative metabolism in the most migratory cells, thereby coordinating lipid droplet breakdown and fatty acid oxidation with cell migration. These data lead to the hypothesis for this proposed research that PDAC cells undergo a metabolic shift to favor the accumulation and storage of lipid droplets, which are catabolized during invasive migration to fuel oxidative phosphorylation to power metastasis. Using a combination of cell biology, biochemistry, and in vivo models, we will test this hypothesis by defining the mechanisms of lipase suppression leading to lipid droplet storage (Aim 1), and the coordinated and localized activation of lipolysis to drive tumor cell invasion (Aim 2). Successful completion of this research will provide fundamental advances in defining the metabolic pathways regulating invasive migration, with a focus on lipid droplets, and with the goal of identifying metabolic vulnerabilities in tumor cells that will provide targets for therapy to block metastasis and improve survival.

转移是癌症死亡的主要原因，然而抑制转移侵袭的治疗策略并不 存在.我们研究计划的长期目标是确定驱动转移的分子机制。 研究的目的是确定新的治疗靶点和策略，以提高癌症的生存率。而 已知肿瘤细胞经历代谢重编程以支持肿瘤生长， 对转移的了解很少。这项拟议中的研究将确定储存的脂质如何用作燃料 胰腺癌转移侵袭的动力来源。我们有初步数据显示胰腺肿瘤细胞 经历向脂质储存的转变，这是入侵所必需的。这是通过抑制 癌基因KRAS引起的激素敏感脂肪酶（HSL），导致脂质积聚和引发肿瘤 细胞转移。这些储存的脂滴然后在侵入过程中通过脂质体被分解代谢。 脂肪酶的作用。这导致大多数迁移细胞的氧化代谢增加，从而 协调脂滴分解和脂肪酸氧化与细胞迁移。这些数据导致 这项研究的假设是PDAC细胞经历了代谢转变，有利于积累 以及储存脂滴，脂滴在侵入性迁移过程中被分解代谢，以促进氧化磷酸化 to power功率metastasis转移.我们将结合细胞生物学、生物化学和体内模型对此进行测试 通过定义脂肪酶抑制导致脂滴储存的机制（目标1）， 协调和局部激活脂解以驱动肿瘤细胞侵袭（Aim 2）。成功完成 这项研究将为确定调节侵袭性肿瘤的代谢途径提供基础性进展。 迁移，重点是脂滴，目标是识别肿瘤细胞中的代谢脆弱性 这将为阻断转移和提高生存率的治疗提供靶点。