A-type lamins restrict cancer cell migration and cell proliferation

The nuclear lamina controls the mechanical properties of the nucleus, its crosstalk with the cell cytoskeleton, and chromatin attachments to the nuclear periphery. The mechanisms by which the nuclear lamina of metastatic tumor cells affect their ability to squeeze through different interstitial and vascular barriers are poorly understood. A-type lamins, lamin A and its splice variant lamin C, are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Since reduced lamin A was reported in some aggressive cancers, we addressed the causal links between downregulated lamin A/C levels and cancer cell migration, survival, and proliferation.

In two metastatic murine cancer lines, B16F melanoma and E0771 breast carcinoma, downregulation of lamin A/C expression dramatically facilitated tumor cell squeezing through small rigid pores. Using a new in vitro transendothelial migration (TEM) assay we found that these tumor cells complete TEM through endothelial junctions irrespective of their relative lamin A/C levels, indicating that the high elasticity of endothelial cells rescues the defective squeezing capacity of nuclei with high lamin A/C expression. Reduced lamin A/C expression only modestly enhanced the emigration of these cells across lung capillaries in vivo. Lowered expression of lamin A/C resulted, however, in reduced constitutive heterochromatin of these cells and increased cancer cell growth in vitro. We are currently testing if lamin A/C regulated transcriptional repression also affects the growth of tumor cells in vivo. Our results suggest that single tumor cells may benefit from downregulating lamin A/C expression both at the level of barrier crossing and proliferation.