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In Vivo Tagging of Lung Epithelial Cells To Define the Early Steps of Tumor Cell Dissemination

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Technical Report,15 Sep 2013,14 Sep 2015

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Trustees of Boston University Boston United States

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Despite the high prevalence and poor prognosis of lung cancer, little is known about the mechanisms of progression. There are two major metastasis paradigms In the classical model, tumors acquire mutations that promote invasive behavior and dissemination late in tumor evolution, whereas in the alternative model, metastasis is an inherent feature of tumors very early in its natural history. A challenge in studying tumor cell dissemination has been the identification of markers that can distinguish cancer cells from cells that normally reside in the bloodstream or at sites of seeding. As a result, there remains uncertainty regarding the mechanisms of metastasis as well as the timing of dissemination. Epithelial-mesenchymal transition EMT, a process by which cells lose epithelial characteristics and develop mesenchymal properties, has been implicated as a means by which tumor epithelial cells acquire the ability to invade and disseminate. Most studies of EMT in the context of cancer biology, however, have been based on cultured cells manipulated in vitro, and thus the relevance of EMT to in vivo carcinogenesis is controversial. If EMT is an early process, then detection methods that rely on cellular expression of epithelial markers alone are unlikely to provide a complete picture of metastasis. To understand the early events that accompany invasive behavior in vivo, we proposed to develop a novel, precise, and sensitive lineage-labeling system to detect and isolate cells of lung epithelial origin during tumor progression in a mouse model of lung cancer. This system will allow us to determine the timing of dissemination during the natural evolution of lung adenocarcinoma in vivo and correlate cell phenotype with the acquisition of invasive and tumor-initiating properties.

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