Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression

Rac1b mediates the matrix metalloproteinase–induced epithelial-mesenchymal transition in lung adenocarcinoma and is a potential therapeutic target in early-stage lung cancer. Neutralizing the Neighbors Life-long addictions to cigarettes—and the accompanying enhanced risk of lung cancer—often begin with a succumbing to peer pressure. Now, Stallings-Mann et al. characterize lung cancer–related peer pressure at the molecule level by showing that a protease in the extracellular matrix compels expression, in neighboring lung cells, of a signaling protein (Rac1B) that acts as a mediator of lung cancer progression. Exposure to cigarette smoke is the key cause of non–small cell lung cancers (NSCLCs), which constitute >80% of all cases of lung cancer. NSCLC is most effectively treated when detected early, but to stop this cancer in its tracks, scientists must learn more about the molecular mechanisms of tumor progression and then use this information to discover new targeted therapies. Rac1b is a tumor-associated, cell-transforming protein that arises as an alternatively spliced isoform of Rac1, a Rho family GTPase that regulates cell proliferation. It has been hypothesized that Rac1b drives oncogenesis by promoting epithelial-mesenchymal transition (EMT), during which epithelial cells detach from each other and from the underlying basement membrane and acquire invasive properties. Matrix metalloproteinases (MMPs) live in and cleave components of the extracellular matrix that borders epithelial cells and have been shown to induce EMT. Stallings-Mann et al. found that expression of mouse Rac1b in lung epithelial cells of transgenic mice spurred both EMT and spontaneous tumor formation. Furthermore, in the transgenic mice, MMP3-induced expression of Rac1b stimulated EMT and progression of the premalignant state in lung epithelial cells to malignant lung adenocarcinoma by bypassing oncogene-induced senescence. In patients, Rac1b mRNA expression was elevated in lung adenocarcinoma relative to adjacent normal tissue, in stage-2 relative to stage-1 lung tumors, and in normal tissue from smokers compared to nonsmokers. How MMP3, Rac1b, and EMT collaborate to drive tumor progression remains unclear. But the new work suggests that drugs that block synthesis or function of Rac1b—which has no known function in normal cells—may prevent progression to late-stage, invasive forms of lung cancer. Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)–induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.