Metastasis is the most devastating phase of tumor progression in all cancers as commonly observed in melanoma. Historically, researchers have focused on tumor phenotype and genotype in seeking strategies that block tumor metastasis. However, evidence accumulated in the past decade supports a crucial role for cells, as well as secreted factors such as cytokines, chemokines and exosomes in the surrounding tumor microenvironment as critical components regulating primary tumor growth and metastatic behavior. The goal of the proposed project is to determine the mechanisms through which tumor-derived microvesicles, known as exosomes and bone marrow-derived cells (BMDCs) promote the highly metastatic phenotype associated with melanoma. We will define the molecular mechanisms, molecules and pathways involved in mediating cross- talk between melanoma-derived exosomes, BMDCs and the metastatic niche microenvironment using complementary in vitro and in vivo models. Since biomarkers predictive of melanoma metastatic progression are lacking, we propose to determine whether exosome cargo and BMDCs can be used as novel indicators of metastatic burden in melanoma. We plan to develop therapeutic strategies to block the activation of pathways, specifically c-MET oncogene signaling, that confer a highly metastatic behavior in melanoma, and that, when up-regulated in hematopoietic progenitors by tumor-derived exosomes, lead to the development of pro- metastatic BMDC subsets. We propose that these strategies will prevent metastasis or hinder its progression by simultaneously reducing the mobilization and recruitment of BMDCs to primary tumor and metastatic niches. The development of novel approaches to analyze the contribution of tumor-derived exosomes to metastasis as well as their capacity to "educate" other cell types is further described in the current proposal. Importantly, we identify novel mechanisms and propose to dissect specific pathways, such as c-MET signaling, involved in BMDC "education" by melanoma exosomes. Our studies in melanoma patients are the first to investigate whether the levels of circulating bone marrow progenitor cells and tumor-secreted exosomes could identify patients with metastatic disease. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic progenitors could block the recruitment of BMDCs and other stroma cell types in melanoma, providing a valuable combination therapy for the management of human disease. Furthermore, we hypothesize that targeting tumor-derived exosome function will contribute to the reduction of metastases and relapses responsible for patient lethality in melanoma, providing a rationale for development of targeted therapeutic approaches. In summary, we will focus on studying the mechanisms through which exosomes regulate BMDC mobilization and recruitment to pre-metastatic and metastatic niches in melanoma models and melanoma patients.
Our proposed studies in melanoma patients are the first to investigate whether the levels of circulating bone marrow-derived progenitor cells, and tumor-secreted microvesicles, also known as exosomes, could identify patients with or at risk for metastatic disease. We propose to explore the possibility that melanoma exosomes activate the c-MET oncogene in bone marrow-derived progenitor cells thus programming these cells to promote melanoma dissemination. Furthermore, we hypothesize that inhibiting c-MET mediated tumor-derived exosome function and bone marrow-derived progenitor cell reprogramming will contribute to the reduction of metastases and relapses responsible for patient lethality in melanoma, providing a rationale for development of targeted therapeutic approaches.
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