Aberrant Store-Operated Calcium Entry (SOCE) in Invasive Melanoma

The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. While easy to treat if diagnosed early, once the cancer has metastasized and spread, it is extremely resistant to current therapies and patient prognosis is poor. Wnt5A has been shown to be a driver of melanoma cell invasion and metastasis. Changes in cytosolic Ca2+ concentration are a key component of Wnt5A signaling and can contribute to both cell proliferation and migration. The main Ca2+ store in the cell is the endoplasmic reticulum (ER). Depletion of ER Ca2+ during cell signaling is sensed by the ER membrane protein STIM1, which interacts with the plasma membrane channel Orai1 to initiate store-operated calcium entry (SOCE) and replenish ER Ca2+. Therefore, we investigated differences in the expression and function of STIM1 and Orai1 in a range of patient-derived malignant melanoma cell lines, previously characterized as either highly invasive (metastatic) or non-invasive. We find that SOCE is diminished in invasive melanoma cells compared to non-invasive cells, although expression levels and localization of STIM and Orai are not perturbed. This represents a novel finding and suggests that aberrant SOCE is a key contributor to melanoma cell invasion and metastasis. Current investigations are focused on defining the mechanism(s) responsible for SOCE suppression in metastatic melanoma, focusing on both how STIM/Orai function is modulated and assessing the potential role of Wnt5A signaling in this process. Completion of these studies will provide critical new insight into cellular mechanisms controlling STIM/Orai function as well as redefining the role of Ca2+ signaling in tumor progression.