FerT Supports the Metabolic Plasticity of Metastatic Lung cancer cells

Introduction

Metastasis is the main cause of death in cancer patients although it is a relatively inefficient process in which only few cells survive the dissemination phase and are capable of resuming malignant growth at distant sites. Metabolic reprogramming is one of the hallmarks of malignant cells in general and metastatic cells in particular, and the resulting acquired metabolic plasticity enables the rapid adjustment of metastatic cells to adverse environment conditions encountered during their dissemination process. The intracellular tyrosine kinases Fer and its sperm and cancer specific variant-FerT accumulate in various subcellular compartments and associate also with complex I of the mitochondrial electron transport chain (ETC) in sperm and cancer cells ^1,2. Furthermore, FerT was shown to potentiate the activity of complex I, under nutrients deprivation conditions ¹. We therefore sought to decipher the roles of Fer and FerT in the metabolic reprogramming and plasticity of metastatic cancer cells.

Materials and methods

Fer and FerT deficient metastatic lung cancer cells (H358) were generated by using a modified crispr-cas9 system. The effect of this knock-out on the metabolic behavior, survival, proliferation and metastatic spreading of the parental and the genetically manipulated cells, was monitored and compared in-vitro and in-vivo.

Results and discussion

We show that Fer and FerT deficient metastatic lung cancer cells exhibit jeopardized metabolic plasticity. This was reflected by severe dependence of the cells on the availability of glucose and their inability to survive and proliferate under glutamine supplied as a major energy generation source. The manipulated cells suffered from impaired mitochondrial complex I activity, decreased mitochondrial membrane potential and elevated levels of ROS production. These were accompanied by the induction of the DNA damage response (DDR) system, onset of apoptosis, elongation of the cell-cycle G2\M phase, and attenuated growth which was exacerbated by the absence of glucose. Notably, cells expressing FerT without the knocked out Fer, regained the metabolic plasticity of the parental cells, indicating the dominant role of FerT in supporting the metabolic plasticity of these metastatic lung cancer cells. Finally, FerT deficient cancer cells formed slowly growing xenografts which failed to metastasize in mice.

Conclusion

The cancer-specific variant of the Fer kinase –FerT, supports the metabolic plasticity and metastatic dissemination of lung cancer cells.

1. Yaffe E. et al. (2014) Cancer Res. 74:6474.
2. Elkis Y. et al. (2017) Nat. Commun. 8: 940.