Lipid Metabolism in Liposarcoma: A Novel Target for Therapeutic Intervention

There is no effective medical therapy for patients with liposarcoma. We find that liposarcomas are dependent upon a constant supply of fatty acids to fuel their growth. Tumors may potentially acquire these lipids by a) de novo synthesis using fatty acid synthase (FASN), b) extracellular hydrolysis of circulating fat using lipoprotein lipase (LPL), followed by cellular uptake using CD36, or c) endocytosis of triglyceride-rich particles using Syndecan-1. We find that liposarcomas express high levels of FASN, LPL, CD36, and Syndecan-1. Moreover, Spot 14, a key nuclear driver of the genes encoding enzymes involved in lipogenesis, is also abundant in liposarcomas. We have demonstrated that the growth of liposarcoma cells is impaired by inhibition of lipid synthesis and is promoted by increased lipid uptake. Our Aims are 1) Identify proteins which interact with Spot 14 in liposarcoma but not in normal adipose tissues. 2) Investigate the functional interactions among the three pathways of lipid acquisition in liposarcoma cells, and determine whether inhibition of one pathway results in upregulation of the others. This work will provide understanding of the mechanisms underlying the exquisite susceptibility of liposarcoma to metabolic manipulation, and will guide the development of novel interventions to control liposarcoma, which is currently curable only by successful surgical resection.