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    Research Grants Awarded

    MMP1-Protease Activated Receptor-1 Signaling in the Tumor-Stromal Microenvironment

    Study Section:
    Tumor Cell Biology I

    Scientific Abstract:
    G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors with more than 1000 members yet only a select few GPCRs exhibit oncogenic activity. Among these, the protease-activated receptor 1 (PAR1) has been identified as an oncogene in the transformation of cells. Moreover, expression of PAR1 is strongly correlated with invasive propensity in breast cancer and many other types of solid tumors. In this grant we test the hypothesis that PAR1 is a critical regulator of cancer-stromal communication, cancer cell growth, tumorigenesis, angiogenesis, invasion and metastasis. We recently identified stromal-derived matrix metalloprotease-1 (MMP-1) as a novel protease agonist that can cleave and activate PAR1 in breast tumors. MMP-1 is highly upregulated in many different types of cancers and is a predictive marker for poor prognosis in breast, colorectal and esophageal tumors. We found that expression of PAR1 was both required and sufficient to promote MMP1-dependent growth and invasion of breast carcinoma cells in xenograft models. Targeting PAR1 with the cell-penetrating pepducins described here blocks the pathway downstream of MMP-1 and receptor inhibiting angiogenesis and cancer growth and invasion. We propose to test whether PAR1 is an effective therapeutic target for blocking tumor-stromal interactions and preventing MMP1-dependent effects. The pepducin approach has the prospect to significantly change our understanding of the role of PAR1 in cancer progression and angiogenesis. As envisioned, these studies will develop the first inhibitors of PAR1 for the potential treatment of invasive and metastatic solid breast cancers. In the tumor microenvironment, stromal and cancer cells are in close proximity to each other. In order to study migration and invasion of stromal and tumor cells that are in direct contact, we will employ a three-dimensional multicellular in vitro tumor model and examine the role of PAR1 in the stromal cells versus the cancer cells using PAR1-null stromal and cancer cell lines. These in vitro studies will be complemented with mouse xenograft models where breast cancer cells and fibroblasts will be co-injected into the mammary fat pads and growth, invasion and angiogenesis assessed over time.

    Lay Abstract:
    G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors with more than 1000 members yet only three GPCRs have been found to be oncogenes. Among these, the protease-activated receptor 1 (PAR1) has been identified as a potent oncogene and confers invasive behavior to pre-cancerous breast cells. In this grant we test the hypothesis that PAR1 is a critical for cancer-host communication, growth, new blood vessel formation, invasion and metastasis. We recently identified host fibroblast-derived matrix metalloprotease-1 (MMP-1) as a novel agonist that can cleave and activate PAR1 in breast tumors. MMP-1 is highly expressed in many different types of cancers and is a predictive marker for poor prognosis in breast, colorectal and esophageal tumors. We found that expression of PAR1 was both required and sufficient to promote MMP1-dependent growth and invasion of breast carcinoma cells in mice. Targeting PAR1 with the novel cell-penetrating pepducins described here blocks the pathway downstream of MMP-1 and receptor inhibiting blood vessel and cancer growth. We propose to test whether PAR1 is an effective therapeutic target for blocking tumor-host interactions and preventing the actions of MMP1. The pepducin approach has the prospect to significantly change our understanding of the role of PAR1 in cancer and blood vessel formation. As envisioned, these studies will develop the first inhibitors of PAR1 for the potential treatment of invasive and metastatic solid breast cancers.