Oscillating calcium levels enable melanoma cells to become invasive, Sun et al. report.
Two proteins, STIM1 and Orai1, are vital for store-operated calcium entry, a process that enables cells to absorb calcium. When calcium levels in the ER dip, STIM1 oligomerizes and travels to the junction between the ER and the plasma membrane. There, it stimulates Orai1 to form a pore in the plasma membrane that admits calcium. Breast cancer cells require STIM1 and Orai1 to metastasize, but the underlying mechanism wasn’t clear.
Sun et al. found that melanoma cells lacking STIM1 and Orai1 sprouted about half as many invadopodia, the extensions that cancer cells use to bore into and dissolve the ECM, as did controls. But it takes more than an influx of calcium to induce the protrusions. Compounds that induce a surge of calcium into cells inhibited invadopodium growth. Instead, invadopodium formation requires oscillating intracellular calcium levels. Depleting STIM1 and Orai1 suppresses these cycles.
Calcium oscillations also promote invasion in another way, the researchers discovered. MT1-MMP, one of the proteases that cancer cells use to dissolve ECM, normally cycles in and out of the invadopodium’s plasma membrane. But depleting STIM1 and Orai1 trapped MT1-MMP inside endosomes, thus preventing the enzyme from recycling to the plasma membrane, where it can attack the ECM.
Why cells rely on oscillations—rather than just an increase—in calcium levels isn’t clear. Large amounts of calcium can be lethal to cells, so one possibility is that the fluctuations prevent it from reaching toxic levels.
Text by Mitch Leslie