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In the Covic laboratory, we study a novel class of cell surface proteins known as protease-activated receptors. These receptors include the major thrombin receptor of blood vessels and platelets as well as receptors that are involved in cancer invasion and metastasis. The first member of the protease-activated receptor family, PAR1, has been identified as an oncogene and its expression correlates strongly with invasive and metastatic processes of cancer cells from breast, melanoma and ovarian tumors.
In addition, we study the downstream signaling molecule, the angiogenesis factor Cyr61, in the malignant progression of breast cancer. Cyr61 was identified as a marker for poor prognosis in a recent large breast cancer study.
Lastly, using in vivo models and precision therapeutic approaches, a major goal is to determine role of PAR4 in platelet reactivity and cardiovascular outcomes.
In the Covic laboratory, we study a novel class of cell surface proteins known as protease-activated receptors. These receptors include the major thrombin receptor of blood vessels and platelets as well as receptors that are involved in cancer invasion and metastasis. The first member of the protease-activated receptor family, PAR1, has been identified as an oncogene and its expression correlates strongly with invasive and metastatic processes of cancer cells from breast, melanoma and ovarian tumors. In addition, we study the downstream signaling molecule, the angiogenesis factor Cyr61, in the malignant progression of breast cancer. Cyr61 was identified as a marker for poor prognosis in a recent large breast cancer study.
Our laboratory studies regulation of matrix metalloproteases (MMPs) and their expression by tumor derived angiogenic factor Cyr61. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. We show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. We hypothesized that tumor-derived Cyr61 may have a global paracrine function in regulating pro-invasogenic lignds (MMPs, chemokines, growth factors) production from adjacent stromal cells which may contribute to tumor invasion through multiple signaling pathways including PAR-1 as schematically shown below.
Figure 1. A schematic of the signaling pathways affected by Cyr61 during tumorigenesis.
Our laboratory also studies breast cancer transformation by PAR-1 with a particular focus on the invasive and metastatic singling mechanisms. PAR1, a G protein coupled receptor, had been previously identified to be a highly potent transforming gene in 2001 (for a review see Whitehead et al, 2001 Abstract) but the mechanism of action of its oncogenic activity was largely unknown. We study ectopic expression of PAR1 in human breast cancer cells induced epithelial-mesenchymal-transition (EMT) and its activation in global gene transcription. We are using PAR-1 ectopic expression system to determine critical signaling for development of invasive and metastatic breast cancer phenotype. Using in vivo mouse xenograft models, our major goal is to identified new therapeutic targets to treat metastatic breast cancer.
The occurrence of life-threatening arterial thrombotic events during acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are critically dependent on reactive platelets. PAR4 was shown to be a significant contributing factor for high thrombotic risk in African Americans and some Caucasians. A genetic contribution to platelet function maps to a single nucleotide polymorphism (SNP) within the coding region of the PAR4 gene. PAR4 Thr120 induced greater signaling, platelet aggregation, but enhanced inhibition by our novel intracellular PAR4 antagonist. Platelet aggregation and calcium mobilization induced by the PAR4 was significantly higher in this population suggesting that blocking PAR4 may provide an unexpected therapeutic benefit. Hyper-reactive platelets may therefore be a contributing factor to both the higher incidence of coronary artery disease in African Americans compared to Caucasian patients and conversely provide an enhanced therapeutic targeting strategy. Using in vivo models and precision therapeutic approaches, a major goal is to determine effect of the single nucleotide polymorphism (SNP) T120A in PAR4 to platelet reactivity and cardiovascular outcomes.
Lidija Covic, PhD
Nga Nguyen, BS
Jim Perkins, MD
Layla Von Doren, MD
View all publications via PubMed
Yang, E., Cisowski, J., Nguyen, N., O'Callaghan, K., Xu, Y., Agarwal, A., Kuliopulos, A., Covic, L. (2016) Oncogene 35:1529-40. Dysregulated Protease Activated Receptor 1 (PAR-1) Promotes Metastatic Phenotype in Breast Cancer through HMGA2. PMID: 26165842
Gurbel, P.G, Bliden, K.P., Turner, S.E., Tantry, U.S., Gesheff, M.G., Barr, T.P., Covic, L., Kuliopulos, A. (2016) Arterioscler Thromb Vasc Biol 36:189-197. Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects with Coronary Artery Disease. PMID: 26681756
Shearer, A.M., Rana, R., Austin, K., Baleja, J.D., Nguyen, N., Bohm, A., Covic, L., Kuliopulos, A. (2016) J Biol Chem. 2016 Oct 28;291(44):23188-23198. Targeting Liver Fibrosis with a Cell-Penetrating PAR2 Pepducin. PMID: 2761387271.
Zhang, P., Covic, L., & Kuliopulos, A. (2015) Methods Mol Biol (2015) 1324:191-203. Pepducins and other lipidated peptides as mechanistic probes and therapeutics. PMID: 26202271.
Zhang, P., Leger, A.J., Baleja, J.D., Rana, R., Corlin, T., Nguyen, N., Koukos, G., Bohm, A., Covic., L., & Kuliopulos, A. (2015) J Biol Chem 290:15785-98. Allosteric Activation of a G Protein Coupled Receptor with Cell-Penetrating Receptor Mimetics. PMID: 25934391.
Foley, C.J., Fanjul-Fernandez, M., Bohm, A., Agarwal, A., Koukos, G., Covic, L., Lopez-Otin, C. & Kuliopulos, A. (2014) Oncogene 33:2264-72. Matrix Metalloprotease-1a Deficiency Suppresses Tumor Growth and Angiogenesis.
Austin, K.M., Covic, L, & Kuliopulos, A. (2013) Blood 121:431-9. Matrix Metalloproteases and PAR1 Activation. PMID: 23086754
Zhang, P., Gruber, A., Kasuda, S., Kimmelstiel, C., O’Callaghan, K., Bohm, A., Baleja, J.D., Covic, L., & Kuliopulos, A. (2012) Circulation 126:83-91. Suppression of Arterial Thrombosis with Affecting Hemostatic Parameters with a Cell-Penetrating PAR1 Pepducin. PMID: 22705889
O’Callaghan K., Kuliopulos A., Covic, L. (2012) J Biol Chem 287:12787-96. Turning Receptors On and Off with Intracellular Pepducins: New Insights into G-protein Coupled Receptor Drug Development. PMCID: PMC3339939
O’Callaghan, K., Lee, L., Nguyen, N., Hsieh, M.-Y., Kaneider, N.C., Klein, A.K., Sprague, K., Van Etten, R.A., Kuliopulos, A. Covic, L. (2012) Blood 119:1717-25. Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. PMID: 22186993
Cisowski J, O’Callaghan K, Kuliopulos A, Yang J, Nguyen N, Deng Q, Yang E, Fogel M, Tressel S, Foley C, Agarwal A, Hunt III SW, McMurry T, Brinckerhoff L, Covic L. (2011) Amer J Pathol, 179:513-23. Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. PMID: 21703428
Kimmelstiel C, Zhang P, Kapur NK, Weintraub A, Krishnamurthy B, Castaneda V, Covic L, Kuliopulos A. (2011) Circ Cardiovasc Interv. 4:171-9. Bivalirudin Is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention. PMID: 21364148
Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A. (2010) Methods Mol Biol. 683: 259-275. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. PMID: 21053136
Agarwal A, Tressel SL, Kaimal R, Balla M, Lam FH, Covic L, Kuliopulos A. (2010) Cancer Res. 70: 5880-5890. Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: Implications for antiangiogenic therapy. PMID: 20570895
Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K, Covic L, Kuliopulos A. (2009) Cell 137: 332-343. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. PMID: 19379698
Nguyen N, Kuliopulos A, Graham RA, Covic L. (2006) Cancer Res. 66: 2658-2665. Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. PMID: 16510585