Breast cancer is a complex disease that kills patients by invading adjacent tissue and spreading to other organs in a process called metastasis. The disease affects about 1 in every 7 women and accounts for over 40,000 deaths in the United States each year, the vast majority of which are due to deadly spread of metastatic cancer cells to organs such as bone and lung. While prevention, diagnosis, and therapy of breast cancer are improving steadily due to intensive research and clinical development efforts, we are still far from being able to cure advanced late-stage cancers. Improved treatments critically rely on better understanding of the molecular mechanisms driving breast cancer metastasis to distant organs.
It has become increasingly clear that interactions between tumor cells and normal organ cells, also called stromal cells, are critical for tumor growth and metastasis. These "tumor-stromal" interactions are often mediated by cellular signaling pathways that relay information from tumor cells to stromal cells, or vice versa. In metastasis, the outcomes of such interactions include molecular changes in distant organs making them more supportive for tumor growth and allowing cancer cells to form full-blown metastatic lesions. Many signaling events between tumor and stromal cells are mediated by secreted molecules, such as proteins, functional miRNAs, and small vesicles, called exosomes. While the role of secreted proteins in bone metastasis has been characterized by our previous studies, their role in lung metastasis remains poorly understood. Moreover, the role of secreted miRNAs and tumor exosomes in both bone and lung metastasis is unclear. Furthermore, it is highly likely that secreted and exosome proteins in tumor-associated stromal cells may also actively participate in the pathogenesis of metastasis.
The proposed study will systemically identify secreted and exosomal proteins and miRNAs from metastatic breast cancer cells and associated stromal cells, and investigate their functional and clinical importance in breast cancer metastasis to bone and lung. We propose to use state-of-the-art technologies such as mass spectrometry and next-generation sequencing to characterize secreted factors. We have previously used mass spectrometry to analyze secreted proteins from highly and lowly bone metastatic cancer cells, and a similar approach will provide us with a complete set of proteins and miRNAs released by lung metastatic cancer cells. A previous study led by co-Principal Investigator (PI) Dr. David Lyden was the first to report the role of tumor exosomes in melanoma metastasis, and we will now perform a comprehensive study of metastatic exosome in breast cancer. Each identified secreted and exosomal factor will be validated in clinically relevant breast cancer cell lines and animal models and its diagnostic, prognostic, and therapeutic value will be assessed in patient serum samples. The proposal is built upon the perfect combination of expertise and research experience of three co-PIs. Dr. Kang, the lead PI and an Era of Hope Scholar, is an expert in the study of breast cancer metastasis, miRNAs, and tumor secretome, and he has a long and productive history of collaborative research with co-PIs Dr. Lyden (expert in exosomes and premetastatic niches) and Dr. Garcia (expert in mass spectrometry). The three laboratories are conveniently located in three elite universities located within a short distance to Princeton and are supported by an extensive network of clinical collaborators and biostatisticians in Memorial Sloan-Kettering Cancer Center, Cancer Institute of New Jersey, and New York-Presbyterian Hospital.
The understanding that we will gain from our studies will have important implications in the diagnosis and treatment of metastatic breast cancer. Due to their extracellular localization, secreted factors represent superior biomarkers and therapeutic targets as they can be readily detected or targeted in blood and other body fluids. Any of the tumor-identified secreted factors with functional role in metastasis and clinical relevance could become a biomarker for metastatic progression or potential metastatic site as well as a target for therapeutic intervention. By better understanding tumor-stromal interactions mediated by secreted and exosomal factors, new treatments can be designed to target stromal cells to prevent or reduce metastasis. In fact, since stromal cells are genetically much more stable than tumor cells, drugs that target tumor-stromal interactions are less likely to become ineffective due to rapid mutations of tumor cells. Our proposed study is likely to benefit almost all breast cancer patients at different stage of disease. Patients with metastatic cancer will benefit from better targeted therapy to slow down or revert disease progression, while patients with localized early-stage breast cancer will have peace of mind with better preventive treatments and sensitive diagnostic markers for early detection of emerging metastasis.
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