Investigating the Metabolic Reprogramming of Ovarian Tumors During Omental Metastasis

摘要

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.