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 invadopodium 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175741-06
Application #
9392538
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2013-12-03
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Zhao, Tiansuo; Jiang, Wenna; Wang, Xiuchao et al. (2017) ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer Res 77:874-885
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
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
Woods, Neha; Trevino, Jose; Coppola, Domenico et al. (2015) Fendiline inhibits proliferation and invasion of pancreatic cancer cells by interfering with ADAM10 activation and ?-catenin signaling. Oncotarget 6:35931-48
Wang, J-Y; Sun, J; Huang, M-Y et al. (2015) STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression. Oncogene 34:4358-67
Sun, Yuefeng; Sun, Jianwei; Lungchukiet, Panida et al. (2015) Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation. Sci Rep 5:11529

Showing the most recent 10 out of 14 publications