RON, a member of the MET proto-oncogene family, has been implicated in the progression of certain epithelial cancers. The purpose of this study was to determine the uncogenic potential of RON in vivo in lung epithelial cells. Transgenic mice were established using surfactant protein C promoter to express human RON in the distal lung epithelial cells. These mice were born normal but developed multiple lung tumors with distinct morphology and growth patterns. Tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple mdules located mostly in the peripheral portions of the lung. A transition from early adenomas to later adenocareinomas was observed. Morphologically, tumors were characterized as enboidal epithelial cells with a lype II cell phenotype, grew along the alveolar walls, and projected into the alveolar septa. RON was highly expressed and constitutively activated in tumors. These results indicate that overexpression of human wild-type RON causes the formatiml of lung tumors with nnique biological characteristics in virtu. This model provides opportunities to stndy the role of RON in the pathogenesis of lung tumors and to elucidate the mechanisms underlying this distinct hmg tumor.