Lung cancer is the most common cause of cancer related deaths in the United States. In 2007 over 160,000 Americans will die from lung cancer, more than from prostate, breast, and colon cancers combined. Approximately 85% of all lung cancers are of non-small cell histology. Although current therapies have marginally improved survival and quality of life for patients with Non-Small Cell Lung Carcinoma (NSCLC), this remains a nearly universally fatal disease. New approaches to drug development and further studies of the biology of this disease are critically needed. Recent data from a large number of laboratories suggest that human cancers are comprised of two distinct populations of cells and are derived from relatively small populations of cancer "stem cells". Normal stem cells have the extraordinary potential to develop into many different cell types in the body. They can theoretically divide without limit to replenish other cells as long as the person or animal is still alive. Maintenance of normal stem cells is tightly regulated by key developmental signal pathways. Many of these same pathways, including the Notch, Wnt, and Hedgehog pathways, appear to be active, but abnormally regulated, in cancers and in defined cancer "stem cell" populations (Reya et al, 2001). In particular, data has shown that high expression of Notch is common in NSCLC (Shaw et al, 2005). Our research group is interested in the potential roles of cancer stem cells in NSCLC and in particular the role of the Notch signaling pathway in driving cancer stem cell survival and growth. We believe that the progression of lung cancer is dependent on a population of cancer "stem cells". Furthermore, we believe that high level Notch signaling defines this population of cancer "stem cells" in, and that inhibition of Notch signaling can inhibit the development and progression of NSCLC. To test these theories, we are using two innovative model systems in which to isolate and characterize "stem cell" populations in NSCLC: a mice model based on activation of K-ras, a common gene abnormality in NSCLC, and a new model based on the fresh transfer of human tumor cells directly from patients to immunodeficient mice (primary heterotransplants). Ultimately, the characterization of a "stem cell" population in NSCLC will help guide the development of targeted therapies against the cells most responsible for recurrent and progressive NSCLC.