Among all cancer-related deaths, breast cancer ranks second in women. Because most breast cancer deaths occur in the metastatic stage, a better understanding of the mechanism of metastatic breast cancer is urgently needed and will improve the survival rate. De novo mutations associated with breast cancer metastasis have been reported by multiple genomic studies, suggesting a selection pressure toward these mutations along the metastatic progression. Recent study has reported that chromosomal instability drives metastasis in breast cancer, suggesting the importance of these genomic variations in the process of metastasis itself. Unfortunately, the mechanisms behind these metastasis associated mutations are unknown.

One possible way to elucidate this gap in knowledge is to decouple the multiple factors in the complex metastasis process, including cell migration and change of extracellular microenvironment, and investigate the impact of these factors on mutation burden. Based on our findings when we induced genomic variations by migrating some cancer lines through micron size constrictions, and our preliminary data on how matrix stiffness modulates DNA repair, we hypothesize that constricted migration of breast cancer cells and change in microenvironment stiffness contribute to the genomic instability that is essential to metastatic progression.

To test this, we aim to: (1) characterize the genomic impact of constricted migration in breast cancer cells, (2) measure genomic mutation and tumor growth variation caused by microenvironment stiffness and (3) determine the role of key regulators that are associated with metastasis-induced genomic instability. We will dissect the progression of breast cancer metastasis from the perspective of mechanobiology and genomics.