Rac1b Activation of Lung Fibrosis and Cancer

Matrix metalloproteinases (MMPs) play a critical role in the development of lung fibrosis and lung cancer. We have previously determined that exposure of mammary epithelial cells to MMPs induces expression of Rac1b, a splice isoform of Rac1 that is 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 MMPs and Rac1b show increased expression in lung tumors and that expression of these genes is associated with a poor prognosis. We have developed transgenic mice which express MMP-3 or Rac1b in lung epithelial cells and have found that these mice exhibit ECM deposition and tissue disruption characteristic of fibrosis as well as accelerated and spontaneous tumor development.

We are currently defining the molecular mechanisms involved in MMP-induced EMT using sophisticated 3D cultures of lung tumor cell lines and primary lung epithelial cells, determining the participation of MMP-induced EMT in fibrosis using a transgenic model in which epithelial cells are permanently tagged and fibrosis is induced by MMP-3, and defining the stage at which MMP expression stimulates tumor progression.