Genomic Instability and the Mechanical Microenvironment

Abstract

Cancer is the leading cause of death in the developed world and the second leading cause of death in the developing world (Jemal., et al., 2011). In order to create more targeted and effective cancer diagnostics and therapies, we first must better understand the biological basis of tumorigenesis and tumor progression. It was recently reported that the tumor microenvironment plays a key role in the progression of cancer by inducing phenotypic changes leading to invasion (Lee et al., 2012). This current project aimed to characterize the effect of the mechanical compliance of a cell’s microenvironment on multinucleation and centrosome amplification, two indicators of genomic instability, which is seen in the progression of all tumors. We found that substrata with high compliance, characteristic of tumor tissue, promote matrix metalloproteinase 3 (MMP3)-induced multinucleation through a reactive oxygen species (ROS)-mediated pathway, while substrata with low compliance, characteristic of normal, healthy tissue, protect against MMP3-induced multinucleation. Our results also suggest that multinucleation may be a major route to centrosome amplification. Future work should investigate the mechanical control of MMP3-induced centrosome amplification and probe additional indicators of genomic instability, such as nuclear shape, DNA oxidation, and mitotic spindle formation.