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Changes in the gene expression of lung tissue occur when the lung is exposed to tobacco smoke. These changes can be responsible for the conversion of healthy lung cells into cancer cells. Exactly how this occurs is not completely known, however, one of the genes thought to be responsible for this process is Snail. This gene is highly expressed in human lung tumors, and it is associated with a poor outcome for patients. We have shown that Snail is also highly expressed in human lung premalignant lesions, tissue at an early stage of cancer development. Lung premalignant lesions are common in current and former smokers, and we believe that some of these lesions develop into lung cancer. It was originally thought that the spread of cancer occurs after a tumor has formed and becomes too large to be self-contained. It has been suggested for tobacco-related cancers that this spread can occur much earlier, prior to tumor formation. This reflects what we see in patients: those with localized lung cancer who undergo surgical removal of the tumor typically return to the clinic within a few years with tumors in distant organs, suggesting that the lung cancer cells traveled to those distant organs very early on, potentially at the same time a tumor was developing.
We have shown that expression of Snail leads to changes in the way normal lung airway cells move: they travel with greater than 50% more speed than cells without Snail. In the proposed studies, we will investigate the role of motility and flexibility in tumor formation and early tumor spread using normal lung airway cells, which can be manipulated to represent cells found in premalignant lesions. We believe that enhanced motility and flexibility in the setting of premalignancy and Snail expression drive tumor initiation and early cell movement to other organs. We anticipate that our investigation will lay the groundwork for new early cancer detection strategies and drug targets for preventative care, both of which could help reduce lung cancer deaths.
In aim 1, we will determine the speed distribution of normal lung airway cells that over-express Snail, and isolate the fastest and slowest moving cells from within this population using a novel selection technique. These isolated fast and slow moving cells will then be tested for their ability to initiate tumor formation in cell-based experiments.
In aim 2, we will investigate the way in which Snail drives enhanced motility by looking at other key genes that are affected when Snail is expressed. We will study what happens to the movement and flexibility of these normal lung airway cells when the expression of these genes are blocked.
We have shown that lung airway cells that express Snail move faster than cells that do not, which likely contributes to tumor initiation and early metastatic behavior. The overarching goal of this research is to determine the contribution of enhanced motility and deformability in the setting of Snail expression to early lung cancer development, and to determine the process by which this occurs. | 