Stephen Baylin, M.D.

We are using a novel model to study how smoking causes lung cancer. Cells chronically exposed to cigarette extract before any lung cancer mutations appear undergo "epigenetic" abnormalities (changes in gene activity that are not caused by changes in the DNA sequence) typical of actual lung tumors. These can inactivate otherwise normal genes that block cancer development. We will develop our model using a novel 3-D miniaturized normal lung. We will insert gene mutations frequently found in lung cancers to determine which epigenetically altered genes are most important in making the cells able to form cancer when mutations arise. This research will lead to a system that can be used to study potential therapy strategies.

Update: We have been able to successfully grow normal human lung epithelial cells, treat them with cigarette extract and evaluate early changes in expression of key epigenetic proteins. We have been successful in establishing a novel 3-D miniaturized normal lung system that even more closely mimics the normal structure of the bronchial epithelium, which may be a critical site where lung cancer originates. To determine which epigenetically altered genes are most important in making the cells susceptible to cancer formation when mutations arise, we have successfully generated a vector tool that can target and prevent expression of four of our candidate epigenetic driver genes simultaneously. We will use this vector to determine which of these genes are important in making the cells more susceptible to cancer formation when a mutation occurs.