Mannose supports lung cancer metabolism during glycolytic limitation

Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. ¹³C₆-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.