Cells within an organism live and grow in environments with a wide range of rigidities, from soft brain tissue to stiff bone tissue. Certain types of cancer cells, however, seem to be “blind” to rigidity, as they can live and proliferate in environments which are too soft for normal cells to grow in. One reason may be that they cannot sense their environment correctly. To develop effective therapies for such diseases that involve defective rigidity sensing, the mechanism of rigidity sensing first needs to be understood. However, capturing real-time rigidity sensing in live cells is challenging because the process is dynamic, transient, and occurs at the molecular scale. Using a combination of nanoscale-manufactured pillar arrays and advanced live-cell imaging to overcome these challenges, the Sheetz lab, in collaboration with the lab of James Hone from the Mechanical Engineering Department at Columbia University, has recently identified the cellular machinery used to test the rigidity of cells’ micro-environment.
When a cell is placed on a substrate made of tiny pillars, it applies forces that pinch a pair of pillars toward each other, and then release them back to a relaxed state. These forces are produced by the cell’s cytoskeleton and transmitted via transmembrane molecules called integrins to the extracellular matrix. In this work it was shown that the pinching force is not a smooth pull and release, but composed of a series of nanometer-scales steps, with a critical pause in the pulling stage at a threshold of ~20 pN. When this force threshold is reached, it triggers recruitment of proteins that promote cell growth. When the substrate is too soft, the force may fail to reach the threshold. In this case, healthy cells will move on to more rigid environments or die off. Cancer cells, however, will remain on the soft substrate and continue to grow as if it was properly rigid. Importantly, a regulatory protein called tropomyosin – which was first identified to play a significant role in regulating force in muscle cells – was identified to control the sensing force which reveals the regulatory mechanism of rigidity sensing. When tropomyosin is removed from normal cells, they begin to grow on soft substrates, i.e., behave like cancer cells. These findings have offered novel insight into how healthy cells sense rigidity and the cause of abnormal rigidity sensing in cancer cells. They are vital to further identifying biological targets that may result in novel therapies for cancer.
The link to the paper: http://www.nature.com/ncb/journal/v18/n1/full/ncb3277.html