Project 461526

Unlike normal cells, cancer cells must support constant growth while being exposed to extreme fluctuations in nutrient and oxygen availability. To achieve this, cancer cells rewire their metabolic programs which distinguishes them from normal cells. Moreover, cancer cells exhibit extraordinary flexibility in switching between different metabolic pathways to meet their bioenergetic needs and provide sufficient amount of building blocks to support their growth. This phenomenon is referred to as "metabolic plasticity" and it plays a major role in adaptation of cancer cells to therapeutic insults and metastatic spread of the disease. Factors that govern metabolic plasticity of cancer cells are incompletely understood. This represents one of the major hurdles in developing efficient therapies to target metabolic vulnerabilities of cancer cells. We have recently discovered a metabolic complex that we refer to as Hydride Ion Transfer Complex (HTC). HTC governs a previously unappreciated metabolic cycle that regenerates electron acceptors while supplying reducing agents that play a central role in in metabolic plasticity, protection of oxidative damage and tumor growth and progression. Based on this we postulated that HTC may play a major role in metabolic plasticity, therapeutic responses and metastatic spread of cancer cells. Further evidence that supports this tenet comes from our studies showing that HTC helps normal cells to become malignant, while the levels of HTC are increased in cancer patient specimens. Altogether, we anticipate that establishing the role of HTC in cancer will provide hitherto unappreciated insights into the mechanisms driving metabolic plasticity of cancer cells and thus in long-term highlight novel therapeutic avenues to target metabolic vulnerabilities of cancer cells.