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; 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，但是抑制转移性侵袭的治疗策略却不 存在。我们的研究计划的长期目标是定义驱动转移性的分子机制 入侵，目的是确定新的治疗靶标和改善癌症生存的策略。尽管 已知肿瘤细胞会经过代谢重编程以支持肿瘤生长，这是代谢驱动因素 转移知之甚少。这项拟议的研究将定义如何将脂质用作燃料 胰腺癌中动力转移性侵袭的来源。我们有胰腺肿瘤细胞的初步数据 经历向脂质储存的转变，这是入侵所必需的。这是通过抑制发生的 癌基因KRAS的激素敏感脂肪酶（HSL）的脂肪酶（HSL），导致脂质积累和启动肿瘤 转移的细胞。然后，这些储存的脂质液滴在侵袭过程中通过 脂肪酶的作用。这会导致大多数迁移细胞中氧化代谢增加，从而 与细胞迁移一起协调脂质液滴分解和脂肪酸氧化。这些数据导致 这项提出的研究假设PDAC细胞经历了代谢转移以有利于积累 和脂质液滴的储存，这些液滴在侵入性迁移中分解为燃料氧化磷酸化 为转移动力。结合细胞生物学，生物化学和体内模型，我们将测试 通过定义脂肪酶抑制的机制，导致脂质液滴储存（AIM 1），并 脂解的协调和局部激活以驱动肿瘤细胞侵袭（AIM 2）。成功完成 这项研究将在定义调节侵入性的代谢途径方面提供基本进步 迁移，专注于脂质液滴，并旨在鉴定肿瘤细胞中的代谢脆弱性 这将提供治疗的靶标，以阻止转移并改善生存率。