AbstractThere is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na⁺/Ca²⁺ signature required for persistent invasion. We identify the Na⁺ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca²⁺ oscillations required for invadopodia formation. Indeed, NALCN‐mediated Na⁺ influx into cancer cells maintains intracellular Ca²⁺ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na⁺/Ca²⁺ exchangers, SERCA and store‐operated channels. This signaling cascade promotes activity of the NACLN‐colocalized proto‐oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.