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Development Project 3: Lung specific Twist-mediated EMT in lung premetastatic niche, Phuoc T. Tran, M.D., Ph.D.
Despite adequate local control, significant morbidity and mortality from breast cancer still occurs primarily from our inability to control metastatic disease. The prevailing hypothesis for metastatic progression of breast cancer incorporates both properties of the seed (or metastatic tumor cell) and soil (or metastatic site) as first posited by Paget . Recent evidence suggests metastatic tumor cells require a receptive microenvironment, or premetastatic niche, at the metastatic site for tumor cell engraftment. Specific stromal cell types and extracellular matrix (ECM) components become enriched at the premetastatic niche. Cancer associated fibroblasts (CAFs), particularly myofibroblasts, have been implicated in the initiation and progression of tumor cells at the primary site, but the role of myofibroblasts at the premetastatic niche has not been adequately investigated. Furthermore, the epithelial-mesenchymal transition (EMT) has been implicated as a potential source of myofibroblasts from transdifferentiation of local epithelial-endothelial cells at the primary tumor site, but the contribution of EMT for the genesis of myofibroblasts at the premetastatic niche is unknown. Twist1 encodes a product that coordinates the EMT process and we have created an inducible mouse model of lung epithelial specific Twist1 expression. Increased metastatic lung burden of transgenic Twist1 mice following experimental metastasis of breast cancer cells would be proof of principle that EMT derived myofibroblasts could be important for development of the premetastatic niche. The central hypothesis is that lung myofibroblasts can be derived from the EMT of lung epithelial cells, and that these resultant myofibroblasts are sufficient to induce a favorable premetastatic niche. Creating a novel preclinical model for proof of principle studies that EMT is a source of myofibroblasts at the premetastatic niche will allow us to test treatments directed against EMT derived stromal cells for metastasis. Finding methods to target both the disseminating tumor cell (or seed) and the premetastatic niche (or soil) is a logical approach to improve outcomes for breast cancer patients.
Aim 1. Determine whether the bi-transgenic Clara cell specific promoter-reverse tetracycline transactivator/Luc-tetO-Twist1 (or CT) mouse line has increased metastatic tumor burden following experimental metastasis with the fluorescently-tagged breast cancer cell line, NT2.5.