title: STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Fujian
authors.initials: F
authors.lastname: Lu
authors.affiliation: 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 shengyu.yang@moffitt.org.
authors.forename: Huifang
authors.initials: H
authors.lastname: He
authors.affiliation: 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 Qingdao Agricultural University, Qingdao 266109, China shengyu.yang@moffitt.org.
authors.forename: Junling
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL 33612.
authors.forename: Jane
authors.initials: J
authors.lastname: Messina
authors.affiliation: Department of Pathology and Cell Biology, University of South Florida College of Medicine, Tampa, FL 33612.
authors.forename: Rahel
authors.initials: R
authors.lastname: Mathew
authors.affiliation: 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.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Amod A
authors.initials: AA
authors.lastname: Sarnaik
authors.affiliation: Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.affiliation: 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 shengyu.yang@moffitt.org.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D015220:Calcium Channels; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019061:src-Family Kinases; D053511:Matrix Metalloproteinase 14; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium