Fer and FerT modulate the Metabolic Plasticity of Metastatic 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 bronchioalveolar 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 impeded growth. Selective knock-out of Fer while maintaining the expression of FerT (H358ΔFer cells), restored the ability of the cells to rely on glutamine supplementation, but impaired their capacity to upregulate compensatory glycolysis. Furthermore, H358ΔFer cells exhibited an increased susceptibility to hypoxic stress. Strikingly, while absence of Fer and FerT significantly attenuated the progression of H358 tumors in-vivo, the presence of FerT without Fer eliminated the growth of the H358 xenografts in mice. Thus, unbalanced expression of Fer and FerT affects metabolic plasticity and impedes the development of metastatic bronchioalveolar NSCLC tumors.