Investigating the Metabolic Reprogramming of Ovarian Tumors During Omental Metastasis

摘要 卵巢癌(OC)是最致命的妇科恶性肿瘤， 大多数与卵巢癌有关的侵袭性转移性疾病 死亡。尽管卵巢癌大网膜转移具有临床意义，但准确的 驱动这种现象的分子机制还没有得到很好的描述， 这使得由此产生的攻击性表型更加令人费解。的长期目标是 这个项目是为了对代谢因素有一个更全面的了解 允许卵巢癌细胞在体内的转移部位定植和增殖 大网膜。我们特别感兴趣的一个方面是戊糖的作用 磷酸途径(PPP)，一种负责产生核苷酸的代谢途径 戊糖前驱体通过一系列非氧化反应和还原 通过一个不同的氧化分支相当于NADPH。我们认为这条途径可能 有助于转移潜能和增殖。以最近的证据为基础 证明卵巢癌细胞经历代谢重新编程以适应 独特的、富含脂质的大网膜环境，我们也认为PPP增加是 被转移细胞适应，作为一种补偿机制。 因此，该项目的总体目标是描述PPP的变化，这些变化是 与大网膜转移有关，在此过程中，癌细胞必须同时调整到新的 微环境利基和迅速扩散。这一点的中心假设是 建议是通过以下途径产生还原等价物和核苷酸前体 PPP满足增殖需求，并维持所需的氧化还原动态平衡 以治疗大网膜转移。以确定是否通过PPP合成核苷酸前体 促进增殖，我将询问氧化分支在 Aim 1的体外和体内模型。在Aim 2，我将使用活细胞 与基因表达的生物传感器相结合的大网膜活体成像 定义转移性定植的氧化还原要求。这项拟议的研究将 允许我们推进我们对新陈代谢现状的集体理解 卵巢肿瘤和代谢重新编程促进的确切方式 转移。这些见解可能会打开针对新陈代谢的治疗途径 漏洞。

ABSTRACT Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of ovarian cancer related deaths. Despite the clinical significance of OC omental metastases, the precise molecular mechanisms which drive this phenomenon have not been well characterized, making the resulting aggressive phenotype even more puzzling. The long-term goal of this project is develop a more comprehensive understanding of the metabolic factors which allow ovarian cancer cells to colonize and proliferate at metastatic sites within the omentum. One aspect we are particularly interested in is the role of the pentose phosphate pathway (PPP), a metabolic pathway responsible for producing nucleotide pentose precursors through a nonoxidative series of reactions and the reducing equivalent NADPH through a distinct oxidative branch. We believe this pathway may contribute to metastatic potential and proliferation. Building on recent evidence demonstrating that ovarian cancer cells undergo metabolic reprogramming to adapt to the unique, lipid rich omentum environment, we also believe that increased PPP is adapted by metastasizing cells as a compensatory mechanism. Thus the overall aim of this project is characterize changes in the PPP which are relevant for omental metastases, during which cancer cells must both adjust to a new microenvironmental niche and proliferate rapidly. The central hypothesis of this proposal is that the generation of reducing equivalents and nucleotide precursors via the PPP meets the proliferative demands and maintains the redox homeostasis required for omental metastasis. To determine if nucleotide precursor synthesis via the PPP promotes proliferation, I will interrogate the importance the oxidative branch using in vitro and in vivo models on omental metastasis in Aim 1. In Aim 2, I will use live-cell intravital imaging of the omentum coupled with genetically-expressed biosensors to define the redox requirements of metastatic colonization. This proposed research will allow us to advance our collective understanding of the metabolic landscape present in ovarian tumors and the precise manner in which metabolic reprogramming promotes metastasis. These insights may open therapeutic avenues to target metabolic vulnerabilities.