Lipid storage and catabolism as drivers of metastatic invasion

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不是。 是存在的。我们研究计划的长期目标是确定驱动转移的分子机制 侵袭，目标是确定新的治疗目标和策略，以提高癌症存活率。而当 已知肿瘤细胞经历代谢重新编程以支持肿瘤生长，代谢驱动因素 对肿瘤转移知之甚少。这项拟议的研究将定义储存的脂肪如何用作燃料 为胰腺癌的转移侵袭提供能量来源。我们有初步数据显示胰腺肿瘤细胞 经历了向脂质储存的转变，这是入侵所必需的。这是通过压制 癌基因KRAS对激素敏感脂肪酶(HSL)的抑制作用，导致脂肪堆积，引发肿瘤 用于转移的细胞。这些储存的脂滴然后在入侵过程中通过 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。这些数据导致了 这项研究的假设是，PDAC细胞经历了有利于积累的代谢转变 和储存脂滴，在侵入性迁移到燃料氧化磷酸化过程中被分解 为转移提供动力。利用细胞生物学、生物化学和活体模型的组合，我们将测试这一点 通过定义脂肪酶抑制导致脂滴储存的机制(目标1)，以及 协调和局部激活脂解以驱动肿瘤细胞侵袭(目标2)。成功完成 这项研究将为确定调节侵袭性的代谢途径提供基础性的进展 迁移，重点是脂滴，目的是确定肿瘤细胞的代谢脆弱性 这将为阻断转移和提高存活率的治疗提供靶点。

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.