A new target to fight disease progression in early stage lung cancers
Researchers from the Mayo Clinic have identified a new therapeutic target that links multiple steps involved in tumor progression and may play a role in the earliest stages of lung cancer. Published this week in Science Translational Medicine, the team has shown that Rac1b can launch lung tumor cells to grow uncontrollably and become invasive.
Rac1b is found in a number of different cancers such as lung, breast and colorectal cancers, and the team found increased levels of Rac1b in tissue samples from smokers with lung cancer or lung disease. Rac1b transmits signals from the Ras family of proteins (including KRas, a known driver of 20-30% of lung adenocarcinomas) and influences a number of different processes that can cause normal cells to develop into tumors.
All in all, this research puts together a clear story: Smoking causes many damaging effects to cells, including increased expression of the cancer-causing protein Rac1b. Activated Rac1b triggers many dangerous processes, leading to invasive behavior and uncontrolled growth of tumors.
Normally, epithelial cells (densely packed cells that make up our skin and surround our organs) avoid invasive behavior because they need to be attached to other cells to grow. Epithelial-to-mesenchymal transition (EMT) occurs when these cells detach from their neighbors and can move about and invade other tissues. Dr. Radisky’s team was able to show that expression of MMP proteins (enzymes that break down epithelial cell scaffolding) can activate Rac1b to promote EMT in lung tissue.
The team was able to take the work a step further, and show that Rac1b activation can help lung tumors break free from cell senescence. Senescence is one of the major protective barriers against cancer and uncontrolled growth in which the cell cycle shuts down and the cell enters a state of permanent stasis. Cells have to find ways to overcome this barrier to transform into tumors and grow limitlessly – in this case through MMP-activated Rac1b triggering EMT.
MMPs have been investigated as targets in the past, but drugs that target MMPs are highly toxic and not effective. Rac1b represents a new target, potentially effective against the early stages of disease. However, Rac1b is in the same family as KRas – they are both GTPases, and we still don’t have an effective clinical agent that can block GTPase activity. Nonetheless, this work connects the dots, and may reveal new targets for future drug development.
M. L. Stallings-Mann, J. Waldmann, Y. Zhang, E. Miller, M. L. Gauthier, D. W. Visscher, G. P. Downey, E. S. Radisky, A. P. Fields, D. C. Radisky, Matrix Metalloproteinase Induction of Rac1b, a Key Effector of Lung Cancer Progression. Sci. Transl. Med. 4,142ra95 (2012).