NALCN‐mediated sodium influx confers metastatic prostate cancer cell invasiveness.

There 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. Synopsis: The contribution of neuronal signaling and ion transport proteins to cancerogenesis remains unclear. Here, the sodium leak channel NALCN is shown to promote metastasis in prostate cancer, mediating Na+‐dependent Ca2+ oscillations critical for invasion.NALCN is enriched in human prostate cancer cell lines and malignant tissues.NALCN mediates cellular Ca2+ oscillations.NALCN‐mediated Ca2+ dynamics trigger secretory remodeling required for Src‐dependent actin dynamics, vesicular secretion of proteolytic enzymes, and invadopogenesis.NALCN depletion impairs prostate cancer cell invasion in vitro and metastasis in vivo. [ABSTRACT FROM AUTHOR]