Malignant assignment of neuronal Na + leak channel, NALCN: governor of Ca 2+ oscillations-encoded invadopodogenesis

Cytosolic Ca oscillations provide signaling input to several effector systems of the cell. These include neuronal development, migration and networking. Although similar signaling events are hijacked by highly aggressive cancer cells, the mechanism(s) driving the ‘neuron-like’ remodeling of the intracellular ionic signature upon cancer progression remains largely elusive. Here, we identify the ‘neuronal’ Na leak channel, NALCN, in metastatic cells at the hot spots of invadopodia formation and Ca event initiation. Mechanistically, NALCN-mediated Na influx associates functionally with plasmalemmal and mitochondrial Na/Ca exchangers (NCX and NCLX), reactive oxygen species (ROS) and store-operated Ca entry (SOCE)/endoplasmic reticulum Ca uptake (SERCA) systems to generate intracellular Ca oscillations. In turn, the oscillatory activity promotes Src-regulated actin remodeling, Ca-dependent secretion of proteolytic enzymes and leads to invadopodogenesis, resulting in tumor progression and metastatic lesions . Thus, we have uncovered malignant assignment of NALCN giving rise to a critical intracellular Na/Ca signaling axis.