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    Research Grants Awarded

    The Role Of Msp In Expanding Breast Tumor Stem Cells And Promoting Metastasis

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Rationale: We discovered that macrophage stimulating protein (MSP) drives metastasis in a mouse model of breast cancer, and is a significant independent prognostic factor for metastasis and death in human breast cancer patients. Thus, the MSP pathway is a potential therapeutic target in breast cancer, and a greater understanding of its function will shed light on future therapies. Our preliminary data suggest that MSP promotes metastasis through expansion of a critical tumor stem cell population. Tumor stem cells have been proposed to be the main driving force, or ?heart? of tumors. These cells are defined by their ability to self-renew, as well as their ability to give rise to the bulk of the proliferating tumor. Importantly, tumor stem cells appear to be resistant to traditional chemotherapy and radiation treatments and, despite shrinkage of the bulk tumor in response to these therapies, the tumor stem cells remain viable and may contribute to relapse of the disease. Therefore, it is critical to identify molecular determinants that regulate tumor stem cell function and may serve as targets for therapy. We believe that MSP is one of these determinants, and we believe that MSP promotes metastasis through expansion of tumor stem cells. Hypothesis: Tumor stem cells contribute to metastasis by virtue of their unique ability to self-renew and seed new tumors, and MSP promotes metastasis through expansion of the tumor stem cell population in breast tumors. Research aims and design: We have developed a unique mouse model for breast cancer that exhibits remarkable metastasis to many organs relevant to human breast cancer. Metastasis in this model is driven by overexpression of MSP. During investigation of the potential mechanisms by which MSP drives metastasis, we observed that tumors from these mice exhibit enhanced characteristics of tumor stem cells, including a 10-fold increased ability to initiate new tumors upon transplantation. Furthermore, human breast tumors that overexpress MSP are more metastatic than those that do not overexpress MSP, and the MSP-expressing tumors contain higher levels of known stem cell genes. Here, we propose to address the connection between MSP and tumor stem cells in metastasis. We will (A) identify the tumor stem cells from mouse mammary tumors in order to study their function, (B) determine the role of these tumor stem cells in metastasis, and determine whether MSP drives metastasis by expanding tumor stem cells, and (C) determine whether MSP functions to expand the tumor stem cell population in primary human breast tumors. Unique advances: Completion of the experiments proposed here will increase our knowledge about tumor stem cell biology and reveal whether these cells contribute to metastasis, which is the leading cause of death in cancer patients. Should MSP be revealed to play a role in expansion of the tumor stem cell population in human breast cancer, it would provide a new potential drug target to inhibit tumor stem cell self-renewal and/or metastasis. Indeed, the MSP pathway is amenable to inhibition with several types of drugs that are already in pre-clinical trials. In another project, we are collaborating with several biotechnology companies and an academic lab to test the efficacy of several new MSP pathway inhibitors against breast tumorigenesis and metastasis.

    Lay Abstract:
    Metastasis, which is the spread of tumor cells from the original tumor to other sites in the body, is responsible for more than 90% of cancer deaths. In breast cancer, this corresponds to more than 40,000 deaths each year in the U.S. alone. Despite its importance, little is understood about the complicated process of metastasis, and there are currently no drugs to block metastasis. Breast tumors are thought to arise from a series of mutations within stem cells in the breast. Stem cells are characterized by their immature state and their unique ability to divide either into additional stem cells, or into mature breast cells. Although it hasn?t yet been proven that breast cancer arises from breast stem cells, several lines of evidence indicate that this is the case: (1) breast tumors are often made up of both immature and mature tumor cells, indicating expansion of a stem cell, (2) only the breast tumor stem cells can generate new tumors when transplanted into mice, and (3) breast tumor stem cells are more resistant to chemotherapy and radiation treatments, which may explain the high failure rate of these therapies. Breast tumor stem cells may also be responsible for metastasis, based on their unique ability to generate new tumors upon transplantation. In addition, tumor stem cells make up the majority of the tumor cells in the bone marrow of breast cancer patients with bone metastasis, indicating that these cells are more capable of giving rise to metastasis. We have discovered a possible link between tumor stem cells and metastasis. We found that macrophage stimulating protein (MSP) drives metastasis in a mouse model of breast cancer, and is a significant early indicator of future metastasis and death in human breast cancer patients. More importantly, inhibiting the MSP pathway might be effective to block metastasis of breast cancer, and a greater understanding of its function is necessary to shed light on future therapies. Our preliminary data, in both mice and humans, suggest that MSP promotes metastasis by increasing the number of stem cells within the tumors. Hypothesis and approach: We propose that tumor stem cells contribute to metastasis by virtue of their unique ability to seed new tumors, and that MSP promotes metastasis of breast cancer through expansion of the tumor stem cell population. We will test our hypothesis by (A) identifying the tumor stem cells from mouse mammary tumors in order to study their function, (B) determining the role of these tumor stem cells in metastasis, and determining whether MSP drives metastasis by expanding tumor stem cells, and (C) determining whether MSP expands the number of tumor stem cells in primary human breast tumor samples donated from patients. Unique advances: Completion of the experiments proposed here will increase our knowledge about tumor stem cell biology and reveal whether these cells contribute to metastasis, which is the leading cause of death in cancer patients. These studies will also reveal important information about how MSP promotes metastasis. Importance to patients: We have already determined that MSP is an important indicator of future metastasis and death in patients with early breast cancer, and that this applies to up to 19% of breast cancer cases (more than 32,000 people per year in the U.S.). If we determine, in these studies, that MSP plays a role in expansion of tumor stem cells in breast cancer, it would provide a new potential drug target to inhibit tumor stem cell growth and metastasis. Indeed, the MSP pathway can be blocked with several types of drugs, some of which are already in pre-clinical trials for other cancers. We are currently testing whether these drugs are effective against breast tumor growth and metastasis. A positive result would warrant a clinical trial with these drugs in breast cancer patients, which could be initiated almost immediately.