Comprehensive Melanoma Research Center, Department of Tumor Biology, Department of Molecular Oncology, Department of Cutaneous Oncology, Experimental Therapeutics Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Comprehensive Melanoma Research Center, Department of Tumor Biology, Department of Molecular Oncology, Department of Cutaneous Oncology, Experimental Therapeutics Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
J Cell Biol. 2014 Nov 24;207(4):535-48. doi: 10.1083/jcb.201407082. Epub 2014 Nov 17.
Ca(2+) 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 Ca(2+) oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca(2+) oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca(2+) 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 Ca(2+)-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca(2+) signals during melanoma invasion and metastasis.
钙离子信号在癌症的侵袭和转移中起着越来越重要的作用，但其中的潜在机制在很大程度上仍不清楚。本文报道了 STIM1 和 Orai1 介导的钙离子振荡通过协调侵袭伪足的组装和细胞外基质（ECM）的降解来促进黑色素瘤的侵袭。钙离子振荡信号通过激活Src 促进侵袭伪足前体的组装。钙离子振荡的破坏抑制了侵袭伪足的组装。此外，STIM1 和 Orai1 调节单个侵袭伪足的蛋白水解活性。在机制上，Orai1 阻断抑制了 MT1-基质金属蛋白酶（MMP）向质膜的循环，并将 MT1-MMP困在内吞小体中，从而抑制 ECM 的降解。STIM1 的敲低显著抑制了异种移植小鼠模型中的黑色素瘤肺转移，表明该途径在转移扩散中的重要性。我们的发现为钙介导的癌细胞侵袭提供了一个新的机制，并为黑色素瘤侵袭和转移过程中储存操作钙信号的时空组织提供了新的认识。
