Fer and FerT sustain the metabolic plasticity of metastatic non-small cell lung cancer cells

Metabolic reprogramming and acquired metabolic plasticity are hallmarks of the ability of metastatic cancer cells to survive and disseminate under hostile and stressful growth conditions. Therefore, deciphering these processes is of great importance and bears potential translational and therapeutic implications. The intracellular tyrosine kinases Fer and its sperm and cancer specific variant, FerT, accumulate in various subcellular compartments and associate with complex I (Comp. I) of the mitochondrial electron transport chain (ETC) in sperm and cancer cells. Here, we show that metastatic non-small cell lung cancer (NSCLC) cells (H358) devoid of Fer and FerT (H358ΔFer/ΔFerT), are strictly dependent on glucose supplementation and exhibit an elevated glycolytic flux. Unlike their parental cells, H358ΔFer/ΔFerT cells fail to rely on glutamine for their growth, and in the absence of glucose they demonstrate increased ROS production and induction of a DNA damage response. This response was accompanied by onset of apoptosis and attenuation of cell-cycle progression, thereby leading to a severely impaired growth. Selective knock-out of Fer while maintaining the expression FerT, restored the ability of the cells to rely on glutamine supplementation, but impaired their capacity to upregulate compensatory glycolysis under hypoxic conditions. Notably, cells lacking Fer and FerT failed to upregulate Hif1/2 alpha under hypoxia. Strikingly, while absence of Fer and FerT severely attenuated the progression of H358 tumors in-vivo, the presence of FerT without Fer eliminated the growth of NSCLC xenografts in mice. Thus, unbalanced expression of Fer and FerT impedes the development of metastatic NSCLC tumors.