Our long term goal is to define the mechanistic roles of store-operated calcium entry (SOCE) in tumor invasion and metastasis. In this research plan we focus on the role of SOCE in the regulation of invadopodium formation, extracellular matrix degradation and melanoma metastasis. Metastasis is responsible for more than 90% of cancer-related death and there are few treatment options available for metastatic cancer. One essential characteristic for metastatic cells is enhanced motility and invasiveness, which helps tumor cells to overcome barriers imposed by basement membrane and surrounding tissues. It is believed that tumor cells use invadopodia to co-ordinate invasion and ECM degradation. Our recent preliminary studies in melanoma support a model whereby SOCE is locally activated to initiate invadopodium formation, ECM degradation and metastasis through a Ca2+-Pyk2-Src pathway. The expected results from Aim1 will define the spatio-temproal organization of SOCE-mediated Ca2+ signals during invadpodium formation and 3D melanoma invasion. Since the intricate organization of Ca2+ in space, time and concentration is the most critical aspect of Ca2+ mobilization that determines the speed, specificity and robustness of Ca2+ signals, and there is virtually no report on the spatio-temporal regulation of Ca2+ signaling during tumor invasion or metastasis, our anticipated results will bring significant insights into Ca2+ mobilization in disseminating melanoma cells. The successful completion of Aim 2 and 3 will define a novel SOCE-Pyk2-Src pathway in melanoma invasion and metastasis and shed new lights on how deregulated SOCE promote melanoma progression. Importantly, we will use novel selective SOCE blocker GSK-7975A to inhibit the invasion and metastasis of human melanoma single cell suspensions directly isolated from patients with metastatic melanoma. The success of the proposed study will provide a proof of concept for targeting SOCE pathway to intervening melanoma metastasis.
This project investigates the basic mechanisms underlying tumor invasion and extracellular matrix degradation during metastasis, which accounts for more than 90% of cancer-related death. The knowledge gained through this proposal will also have significant implications for other physiological and pathological conditions involving invasion and extracellular matrix remodeling, such as arthritis, atherosclerosis, bone reabsorption, immune surveillance, etc.
|Mo, Pingli; Yang, Shengyu (2018) The store-operated calcium channels in cancer metastasis: from cell migration, invasion to metastatic colonization. Front Biosci (Landmark Ed) 23:1241-1256|
|Lu, Fujian; Sun, Jianwei; Sun, Tao et al. (2018) Fluorescence-Based Measurements of Store-Operated Ca2+ Entry in Cancer Cells Using Fluo-4 and Confocal Live-Cell Imaging. Methods Mol Biol 1843:63-68|
|Keeley, Tyler; Lin, Shengchen; Lester, Daniel K et al. (2018) The fucose salvage pathway inhibits invadopodia formation and extracellular matrix degradation in melanoma cells. PLoS One 13:e0199128|
|Huang, Chongbiao; Li, Na; Li, Zengxun et al. (2017) Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression. Nat Commun 8:14035|
|Wang, X; Lang, M; Zhao, T et al. (2017) Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma. Oncogene 36:3048-3058|
|Emmons, Michael F; Anreddy, Nagaraju; Cuevas, Javier et al. (2017) MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma. Sci Rep 7:2685|
|Zhao, Tiansuo; Jiang, Wenna; Wang, Xiuchao et al. (2017) ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer Res 77:874-885|
|Sung, Hyeran; Kanchi, Krishna L; Wang, Xue et al. (2016) Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. Oncotarget 7:23885-96|
|Lin, Shengchen; Lu, Shuang; Mulaj, Mentor et al. (2016) Monoubiquitination Inhibits the Actin Bundling Activity of Fascin. J Biol Chem 291:27323-27333|
|Wang, Xiuchao; Ren, He; Zhao, Tiansuo et al. (2016) Single nucleotide polymorphism in the microRNA-199a binding site of HIF1A gene is associated with pancreatic ductal adenocarcinoma risk and worse clinical outcomes. Oncotarget 7:13717-29|
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