Our collaborative project expands on the concept of 'metastatic niche'as an important determinant of malignancy in the breast. Over the past decade, we have enhanced our conceptual understanding of the microenvironment as a potential driver of tumor growth and metastasis. Our next challenge is to dissect the precise cellular interactions that drive malignant behaviors of susceptible epithelial cells in the breast s well as their secondary homes (i.e., those that they disseminate to, and where they sit in a 'dormant'fashion waiting to strike again). Based on Dr. Lyden's groundbreaking recognition and molecular dissection of the pre-metastatic niche and Dr. Bissell's pioneering analysis of cell-extracellular matrix (ECM) interactions specifying normal versus malignant behavior and the crucial role of the microenvironmental regulation of breast tumors, we conceive of niches within primary and secondary tumor sites. These are governed by the crosstalk between breast tumor cells and their stroma that is mediated by secreted factors like chemokines/cytokines, ECM components, and exosomes, which contain both classes of molecules. Specifically, we hypothesize that exosome-mediated crosstalk in the primary tumor microenvironment and within the bone marrow microenvironment facilitates tumor progression. Since biomarkers predictive of breast cancer (BC) progression and metastasis are lacking, we propose to isolate exosomes (poorly studied small vesicles surrounded by membranes and full of proteins and RNA that are released by tumor cells that could cause potential harm) from BC patients and healthy controls to determine whether exosome content are predictive of patient stage, metastatic burden and survival. We will define proteomic signatures of breast tumor-derived exosomes that can be used clinically for diagnosis and may provide therapeutic targets. We will also utilize 3-dimensional co-culture models to determine how malignant progression and concomitant disruption of tissue architecture influences the exosome release and incorporation of potentially malicious content. The function of these exosomes will be tested by measuring their ability to activate neighboring 'normal'breast stromal cells and to elicit reciprocal tumor-promoting functions from these cells. Finally, we will utilize animal models and 3D co-cultures to measure BC exosome interaction with bone marrow cells and whether exosomes elicit formation of pre-metastatic niches within the bone marrow or disrupt dormant niches within the tissue. All the proposed studies will keep a therapeutic focus by targeting protein content within exosomes to determine whether doing so eliminates tumor-promoting effects. The long-term objectives of our work are to identify targetable molecules contained within exosomes to hinder tumor progression and halt metastatic relapse.
There are a growing number of studies demonstrating tumor-derived microvesicles, referred to as exosomes, may alter the tumor microenvironment, but by what mechanism, and whether their role is significant in tumor progression remains unknown. The goal of our proposal is to establish the clinical, biological and functional relevance of breas cancer-derived exosomes in both progression of primary tumors and metastasis, and to establish whether exosomes found in premetastatic niches contain unique cargos that are therapeutically targetable. We will combine analysis of clinical specimens, animal models and 3-dimensional bioengineered co-cultures to address these questions in depth.
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