This application is a resubmission for an individual fellowship for an MD-PhD student, with a research training plan designed to aid her long-term goal of becoming an independent physician-scientist. The applicant is a student in the Medical Scientist Training Program at the University of Pennsylvania Perelman School of Medicine and would greatly benefit from this award in achieving her career goals in the field of Cancer Biology. The focus of this project is to understand the role of stromal cells in promoting metastasis in the lung. Metastatic disease is responsible for 90% of cancer deaths, yet few effective treatments for widespread metastasis currently exist. The microenvironment has been suggested to play an important role in priming distant sites for metastasis, but the contribution of stromal populations in early metastatic sites in the lung is not well understood. This proposal focuses on the role of stroma in lung metastasis. Stromal cells in metastatic sites undergo activation; activated fibroblasts express fibroblast activation protein (FAP) and/or the myofibroblast marker ?-smooth muscle actin and secrete and remodel extracellular matrix (ECM). However, the kinetics and mechanisms underlying fibroblast activation have not yet been assessed in early metastatic sites in the lung. I will specifically investigate the role of the calcineurin (CN)/NFAT signaling pathway in the activation of lung fibroblasts in the early stages of metastatic seeding and expansion in the lung. The CN/NFAT pathway plays an important role in the tumor microenvironment; published studies and my preliminary data indicate that it may mediate the activation of tumor stroma. CN is a calcium-responsive serine/threonine phosphatase that dephosphorylates NFAT, promoting its nuclear localization and transactivation of genes. Our lab has shown that CN/NFAT signaling is activated in endothelial cells (ECs) at early metastatic sites in the lung, and global genetic deletion of an endogenous CN inhibitor leads to increased metastasis and angiogenesis. CN/NFAT signaling is required for ECM deposition and myofibroblast differentiation in non- malignant states of fibroblast activation but has not yet been studied in cancer. My preliminary data suggest that CN is required for functional stromal activation. This proposal will investigate whether CN/NFAT signaling is required to activate fibroblasts in pre-metastatic sites in the lung, leading to the activation of ECs and the creation of a permissive microenvironment for metastatic colonization and growth in the lung. My studies will better elucidate the biology of CN-NFAT signaling in fibroblasts at metastatic sites and mechanisms underlying metastatic tumor cell colonization in the lung. My findings may also lead to new therapies to prevent widespread lung metastasis.
Most cancer related mortality is due to metastatic disease, when cancer cells leave their primary site and colonize distant tissues. The local microenvironment in these distant tissues is known to play an important role in priming these sites for tumor cells to metastasize, but little is know about the mechanisms underlying fibroblast activation in these sites. Published studies and my preliminary data show that calcineurin/NFAT signaling is important for fibroblast activation; I wil analyze the role of calcineurin/NFAT in fibroblasts in mediating the colonization and expansion of metastatic tumor cells in the lung.
