STIM1- and Orai1-mediated Ca²⁺ oscillation orchestrates invadopodium formation and melanoma invasion

Ca²⁺ signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca²⁺ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca²⁺ oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca²⁺ oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1-matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca²⁺-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca²⁺ signals during melanoma invasion and metastasis.