PROJECT SUMMARY/ABSTRACT Glucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production and as an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucose but only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect), thereby creating an inhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells. However, cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth through unclear mechanisms. My preliminary data revealed that in low glucose conditions, extracellular lactate enhances cancer cell proliferation. Mechanistically, I found that lactate preferentially enters the mitochondria TCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity, which in turn suppresses glycolysis to conserve extracellular glucose, suggesting cancer cells rely on lactate-induced OXPHOS for optimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay between lactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3), and assessing therapeutic potential of targeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determine how lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeutic potential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguish and preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientific expertise gained through these studies will facilitate my transition to independence, with my long-term goal to study and target metabolic vulnerabilities in cancer as a physician scientist. In addition to the scientific goals, I have also outlined a detailed career development plan in this application to obtain skills that are necessary for leading an independent research laboratory. The proposed research and training plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-Kettering Cancer Center, along with the nearby Rockefeller University and Weill Cornell Medical College will provide the ideal academic environment to achieve these goals for me to transition to independence.