The Role of Platelets in Establishing the Lung Pre-Metastatic Niche in Breast Cancer

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PROJECT SUMMARY Tumor metastasis remains responsible for >65% of cancer-associated mortality and nearly all breast cancer deaths. Given the difficulties in treating metastatic disease, preventive approaches that block the successful dissemination of tumor cells to distant organs like the lung offer an attractive and under-researched therapeutic strategy for breast cancer patients at risk of metastatic disease. Primary tumors increase metastatic efficiency by reprogramming the microenvironment of distant organs before the arrival of circulating tumor cells. These tumor- permissive sites are commonly referred to as the “pre-metastatic niche” (PMN) and undergo a series of cellular and structural adaptations that support arriving tumor cells, including the recruitment of inflammation-promoting and immunosuppressive cells, neoangiogenesis, and stromal remodeling. Despite their archetypal roles in hemostasis, blood platelets are integral to inflammatory lung diseases and regulate many of the hallmarks adopted by the PMN. I, therefore, hypothesize that platelets promote the lung PMN. My preliminary data support this statement, demonstrating that platelets are sequestered in pre-metastatic lungs and that lowering platelet counts reduces immune cell recruitment to the lung PMN. To expand on these initial findings, this research will determine the contributions of platelets to the lung PMN (Aim 1), elucidate mechanisms by which platelets impact the lung pre-metastatic environment (Aim 2), and test if therapeutically targeting pre-metastatic platelet number or function impairs metastasis (Aim 3). The technical skills and scientific expertise I will obtain throughout the K99 award period will prove instrumental in my transition into an independent researcher, with the long-term goal to develop novel preventative and adjuvant therapeutic strategies for patients at risk of metastatic breast cancer. To reach these long-term goals, I have outlined a detailed career development plan, which will provide me with the technical and leadership skills to establish a successful research laboratory. The K99 phase of research will be conducted under the excellent (co)mentorship of Drs. Elisabeth Battinelli and Sandra McAllister at the Hematology Division of Brigham and Women’s Hospital. My Research Advisory Committee and collaborators are leading experts in the breast cancer PMN (Dr. Moses), platelet production (Dr. Italiano), and targeting platelets for breast cancer therapy (Dr. Chen). This K99/R00 award will provide me unparalleled support for my successful transition to an independent investigator studying platelet and cancer biology.