Matrix Metalloproteinases in Lung Cancer

Matrix metalloproteinases (MMPs) play a critical role in the development of lung fibrosis and lung cancer. Our lab has already determined that exposure of mammary epithelial cells to matrix metalloproteinases induces expression of Rac1b, a splice isoform of Rac1 that's found in many different tumor types. We have also determined that MMP-induced Rac1b stimulates a specialized form of epithelial-mesenchymal transition (EMT) in which the cells acquire myofibroblast-like characteristics.

Our preliminary examination of human lung tumor tissue samples revealed that matrix metalloproteinases and Rac1b show increased expression in lung tumors and that expression of these genes is associated with a poor prognosis. Our lab team has developed transgenic mice that express MMP-3 or Rac1b in lung epithelial cells. These mice exhibit extracellular matrix (ECM) deposition and tissue disruption characteristic of fibrosis and accelerated and spontaneous tumor development.

We're now defining the molecular mechanisms involved in MMP-induced epithelial-mesenchymal transition using sophisticated 3D cultures of lung tumor cell lines and primary lung epithelial cells. We're working to determine the participation of MMP-induced epithelial-mesenchymal transition in fibrosis using a transgenic model in which epithelial cells are permanently tagged and fibrosis is induced by MMP-3. We're also defining the stage at which MMP expression stimulates tumor progression.