The Role Of Nuclear Deformation And Rupture In Breast Cancer Cell Migration

Invasion of tumor cells into the surrounding tissue is a critical step in the metastatic cascade, which is responsible for the vast majority of cancer-related deaths. Recent findings have begun to demonstrate that the biophysical properties of the cell nucleus play a critical role in this process. During invasion, cancer cells must often pass through interstitial spaces much smaller than the cell nucleus. While the cell cytoplasm easily maneuvers through confined spaces, the deformability of the nucleus, which is the largest and stiffest organelle, ultimately determines how efficiently a cell can pass through a tight space. Furthermore, as the nucleus deforms to move through a confined space, it can exhibit transient loss of nuclear envelope (NE) integrity, where the nuclear membranes rupture and nuclear and cytoplasmic components interchange. We previously showed that chromatin is exposed to the cell cytoplasm during NE rupture, and cells can incur DNA damage. While this work revealed that cancer cell migration requires nuclear deformation and can involve NE rupture, it is currently unknown whether such events correlate with metastatic potential. We used a panel of human breast cancer cells lines, including claudin-low, basal-like, and lumen-like cells. Cells were stably labeled with a green fluorescent protein fused to a nuclear localization sequence (NLS-copGFP) to investigate whether some cell lines were particularly well suited to migrate through tight spaces, and if any were particularly prone to NE rupture. The cells were loaded into microfluidic devices that were designed to mimic interstitial in vivo spacing and monitored by time-lapse microscopy. Devices contained constrictions 5 µm tall and 1, 2, or 15 µm wide. We found that claudin-low cell lines such as BT-549 migrated through confined spaces (1+2 µm wide constrictions) significantly faster and more efficiently than basal-like HCC70 cancer cells. In contrast, the various cell lines displayed similar migration rates in the 15 µm wide constrictions, which do not require nuclear deformation. Thus, the differences observed between the cell lines reflect specific defects in migration through confined spaces, and not general migration defects. We are currently expanding our studies to a larger panel of cancer cell lines and to mouse breast cancer models. If confirmed, these results could indicate that highly invasive cancer cells may benefit from more deformable nuclei that facilitate movement through tight spaces encountered in the tissue microenvironment. Citation Format: Alexandra L. McGregor, Joshua J. Elacqua, Emily S. Bell, Jan Lammerding. The role of nuclear deformation and rupture in breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1897. doi:10.1158/1538-7445.AM2017-1897