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Molecular Oncology Research Institute (MORI)

Covic Laboratory

Lidija Covic, PhD, Prinicipal Investigator at MORI, Tufts Medical Center 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.

Protease-Activated Receptors in Cancer and Vascular Cell Biology

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.

Matrix Metalloproteases and Cyr61 in Tumorigenesis

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.

The Role of PAR1 in Metastasis

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.

CXCR4 Antagonism in Stem Cell Mobilization, Chemosensitization and Metastasis

A subset of cancer cells might have unique quality that may propel metastasis of tumors.  Stromal cell-derived factor-1 (SDF-1 also know as CXCL12) and its receptor CXCR4 play a central role in both of these processes. Disruption of the SDF1a/CXCR4 interaction releases hematopoetic stem cells from the bone marrow into peripheral blood. Here, we use pepducin technology to target intracellular loops of CXCR4 (see Figure 2) in order to develop new generation of inhibitors for studies in cancer.

Figure 2. The structural model of the 7-transmembrane CXCR4 receptor illustrating the targeted intracellular loops.

Lidija Covic, PhD
Nga Nguyen, BS

View all publications via PubMed

Foley CJ, Luo C, O’Callaghan K, Hinds P, Covic L, Kuliopulos A. 2012. Matrix metalloprotease-1a promotes tumorigenesis and metastasis. J Biol Chem. in press.

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. Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer. Amer J Pathol, in press.

Kimmelstiel C, Zhang P, Kapur NK, Weintraub A, Krishnamurthy B, Castaneda V, Covic L, Kuliopulos A. 2011. Bivalirudin Is a dual inhibitor of thrombin and collagen-dependent platelet activation in patients undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. Epub ahead of print. Abstract

Dowal L, Sim DS, Dilks JR, Blair P, Beaudry S, Denker BM, Koukos G, Kuliopulos A, Flaumenhaft R. 2011.  Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc Natl Acad Sci USA 108: 2951-2956.  Abstract

Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A. 2010. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol Biol. 683: 259-275. Abstract

Agarwal A, Tressel SL, Kaimal R, Balla M, Lam FH, Covic L, Kuliopulos A. 2010. Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: Implications for antiangiogenic therapy. Cancer Res. 70: 5880-5890. Abstract

Swift S, Xu J, Trivedi V, Austin KM, Tressel SL, Zhang L, Covic L, Kuliopulos A. 2010. A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization. J Biol Chem. 285: 11402-11410. Abstract

Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K, Covic L, Kuliopulos A. 2009. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137: 332-343. Abstract

Agarwal A, Covic L, Sevigny LM, Kaneider NC, Lazarides K, Azabdaftari G, Sharifi S, Kuliopulos A. 2008. Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer. Mol Cancer Ther. 7: 2746-2757. Abstract

Hatziapostolou M, Polytarchou C, Panutsopulos D, Covic L, Tsichlis PN. 2008. Proteinase-activated receptor-1-triggered activation of tumor progression locus-2 promotes actin cytoskeleton reorganization and cell migration. Cancer Res. 68: 1851-1861. Abstract

Kaneider NC, Leger AJ, Agarwal A, Nguyen N, Perides G, Derian C, Covic L, Kuliopulos A. 2007. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nat Immunol. 8: 1303-1312. Abstract

Leger AJ, Covic L, Kuliopulos A. 2006. Protease-activated receptors in cardiovascular diseases. Circulation 114: 1070-1077. Abstract

Nguyen N, Kuliopulos A, Graham RA, Covic L. 2006. Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Res. 66: 2658-2665. Abstract

Leger AJ, Jacques SL, Badar J, Kaneider NC, Derian CK, Andrade-Gordon P, Covic L, Kuliopulos A. 2006. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation 113: 1244-1254. Abstract

Kimmelstiel C, Badar J, Covic L, Waxman S, Weintraub A, Jacques S, Kuliopulos A. 2005. Pharmacodynamics and pharmacokinetics of the platelet GPIIb/IIIa inhibitor tirofiban in patients undergoing percutaneous coronary intervention: implications for adjustment of tirofiban and clopidogrel dosage. Thromb Res. 116: 55-65. Abstract

Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. 2005. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120: 303-313. Abstract