This proposal outlines a 5-year training program for the development of an independent career in cancer research. The candidate is trained in Anatomic Pathology and has a Ph.D. in Molecular and Cellular Biology. The mentor is Tyler Jacks, director of the Koch Institute for Integrative Cancer Research and Professor of Biology at the Massachusetts Institute of Technology. Dr. Jacks is a world leader in the use of sophisticated mouse models to dissect the molecular basis of tumorigenesis. In the short term, the proposed research program will provide training in the use of genetically engineered mouse cancer models, a new field of research for the candidate. This training program will prepare the candidate to become an independent physician-scientist, with a long term research program that integrates studies of primary human tumors with mouse models of cancer. The candidate will pursue a program of both basic and translational research to develop new diagnostics and therapeutics for cancer patients as quickly as possible. Lung cancer is the most frequent cause of cancer death worldwide, with lung adenocarcinoma being the most common type. The transcription factor Nkx2.1 (TTF1) has a dichotomous function in lung adenocarcinoma, promoting the growth of some tumors but inhibiting others. The overall goal of this proposal is to delineate the mechanisms by which Nkx2.1 regulates tumorigenesis. This will be achieved by using a conditional allele of Nkx2.1 to study its function in a mouse model of Kras-driven lung adenocarcinoma. Results will then be integrated with studies of primary human lung tumors and cell lines. Preliminary data show that Nkx2.1 directly regulates the differentiation and malignancy of tumors in a mouse model of lung adenocarcinoma. The specific aims of the proposal are: 1) Define the function of Nkx2.1 in the normal cells that give rise to lung adenocarcinoma, 2) Define the role of Nkx2.1 in lung adenocarcinoma initiation and progression, and 3) Identify Nkx2.1 target genes that regulate the malignant potential of lung adenocarcinoma. These experiments will test the hypothesis that Nkx2.1 imposes a lineage-specific differentiation program on lung adenocarcinomas and thereby modulates several hallmarks of cancer, including proliferation, invasion and metastasis. It is expected that this work will facilitate the design and testing of new therapeutics that specifically target lung adenocarcinomas based on the activity of the Nkx2.1 transcription factor.