Fer and FerT support the Metabolic Plasticity of Metastatic Rhabdomyosarcoma cancer cells

Reprogrammed metabolism and altered energy generation pathways are hallmarks of the abnormal survival of malignant cells. Cancer cell mitochondria are reprogrammed to support the metabolic needs of malignant cells. Fer and FerT were recently reported as players in the mitochondrial reprogramming in cancer cells. In order to better understand the roles of Fer and FerT in the reprogrammed metabolism of metastatic rhabdomyosarcoma cells, we examined the survival of SJSCRH30 cells under different nutrient condition.

Here we describe the application of the CRISPR/CAS9 gene editing system for the generation of Fer/FerT deficient, metastatic SJSCRH30DFer/FerT cells.

Fer and FerT deficiency significantly affected the ability of SJSCRH30∆Fer/FerT cells to survive under restricted nutrient conditions (cells were supplied with 1g/L glucose as a sole nutrient). Since no difference was observed in the lactate level secreted by the native and SJSCRH30∆Fer/FerT cells, we conclude that Fer and FerT are not implicated in glycolysis progression in these Rhabdomyosarcoma cells. Avoiding glycolysis and supplying the cells with glutamine alone to propel mitochondrial phosphorylation (Oxphos), led to the upregulation of the metabolic sensor adenosine-mono-phosphate protein kinase (AMPK) and its downstream effector PGC1a, in SJSCRH30∆Fer/FerT cells. Furthermore, glutamine supply restored the survival ability of SJSCRH30∆Fer/FerT cells. Thus, shifting the metabolic and energy generation processes from glycolysis to oxidative Oxphos, activates stress sensing cascades that alleviate the dependence of SJSCRH30 cells on Fer and FerT.

These findings suggest participation of the Fer and FerT kinases in several key metabolic processes which contribute to the aberrant growth of malignant Rhabdomyosarcoma cells.