The objective of this proposal is to determine the functions of breast cancer cell-secreted exosomes in regulating tumor motility, stemness, and immune evasion. Our preliminary results demonstrate that circulating tumor cells (CTCs) aggregate to form clusters and promote stemness for polyclonal metastases in triple negative breast cancer (TNBC) (Cancer Discovery, 2019). We also found that cancer exosomes induce the clustering and migration of tumor recipient cells. Educating human leucocytes with cancer exosomes inhibit immune cells, and suppress its tumor-killing effects. A growing body of evidence highlights the role of exosomes in cellular communications, and regulatory effects of exosomal proteins on metastatic niche and tumor immune microenvironment; however, the role of cancer exosomes in cancer stemness and immune regulation is not elucidated. We hypothesize that cancer exosomes promote metastasis of breast tumor cells and suppress neutrophil-mediated anti-tumor immunity in TNBC. In order to test our hypothesis we will: 1) examine the role of tumor exosomes in the stemness of tumor recipient cells and 2) determine the role of cancer exosomes in neutrophil suppression. We have optimized protocols to isolate exosomes, characterize them, and perform functional studies. Human patient-derived xenograft (PDX) models, MDA-MB-231 cells, and mouse breast tumor models E0771 and 4T1 will be used to examine the functions of cancer exosomes. Human and mouse immune cells will be isolated from the blood for exosome education and tumor-immune cell interaction analyses. Taken together, this study aims to determine if cancer exosomes serve as a new therapeutic target for both stemness and immunosuppression in TNBC.
Triple negative breast cancer (TNBC) is highly metastatic and is considered the most aggressive breast cancer subtype. Breast tumor initiating cells promote tumorigenesis, metastasis and immune suppression. This study aims to determine if cancer exosomes serve as a new therapeutic target for both stemness and immunosuppression in TNBC.
