Intracellularly-derived lysophosphatidic acid (LPA) and glycerophospholipid metabolism in ovarian cancer

• Applicant: Rosemarie Marchan, Ph.D.
• Subject Area: Gynaecology and Obstetrics ; Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493593710

Ovarian cancer has one of the highest fatality rates among female gynaecological cancers. A main reason for the overall poor prognosis is the often late diagnosis due to unspecific symptoms early in the disease and a lack of early diagnostic markers. Treatment options are available; however, development of resistance often results in decreased drug efficacy, making a cure difficult. Thus, a more systematic characterization of the underlying mechanism of ovarian cancer development and progression is needed. Alterations to cellular metabolism is a relevant factor in tumorigenesis as cancer cells rewire how they produce and use energy, alter lipid metabolism for membrane and cytoskeleton restructuring, and deregulate signalling pathways that control cell behaviour. In our previous work, we showed that mitochondrial glycerol-3-phosphate acyltransferase (GPAM) is associated with worse survival in ovarian cancer. GPAM esterifies long-chain fatty acyl coenzyme A to glycerol-3-phosphate producing lysophosphatidic acid (LPA), which has been reported to be elevated in the plasma and ascites of ovarian cancer patients, and is thus a proposed biomarker. We showed that silencing GPAM in different cell lines led to reduced migration, decreased intracellular LPA levels, and slowed tumor growth in a subcutaneous xenograft model. In subsequent experiments, knocking down acylglycerol kinase (AGK), a second enzyme that produces LPA in cells also decreased cell migration in ovarian cancer cell lines. LPA is a key intermediate in glycerophospholipid synthesis, as well as a signalling lipid that regulates processes, such as cell migration, proliferation and angiogenesis. However, all studies to date have focused on extracellular LPA that mediates signalling by binding to receptors on the outer cell membrane. There is almost no information on the role of intracellularly-derived LPA and cell function. Thus, in the present application, we aim to comprehensively investigate how intracellularly-derived LPA regulates cancer-related phenotypes using in vitro and in vivo models of ovarian cancer. We also begin elucidating the mechanism by which intracellular LPA influences these phenotypes. Our main questions are: i) How do perturbations to the key enzymes that directly metabolise intracellular LPA affect cancer-related processes, such as cell migration, invasion, adhesion, and viability, as well as the levels of related lipids and metabolites in ovarian cancer cell lines? ii) Does intracellularly-derived LPA regulate cellular processes by being exported from the cell and binding LPA receptors at the plasma membrane?iii) Does intracellularly-derived LPA impact tumour growth and metastasis in vivo in animal models of ovarian cancer, and how representative are our findings to the human disease?

• DFG Programme: Research Grants
• Co-Investigator: Karolina Edlund, Ph.D.