Journal
JOURNAL OF CELL BIOLOGY
Volume 207, Issue 4, Pages 535-548Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201407082
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Funding
- National Cancer Institute [R01CA175741, P50CA168536, P30-CA76292-14]
- Major State Basic Research Program of China [2013CB531200]
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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 Orail-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 Orai 1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orail 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.
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