Reduced nuclear lamin A/C enhances cancer cell squeezing through rigid barriers, does not facilitate endothelial crossing, and impairs experimental metastasis

The mechanisms by which the nuclear lamina of tumor cells control their migration and survival are poorly understood. Lamin A and its splice variant lamin C are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Genetically reduced lamin A/C levels in two metastatic murine cancer lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, elevated nuclear deformability, reduced H3K9Me3 heterochromatin, and altered gene transcription. Nevertheless, the transendothelial migration capacity of lamin A/C low cells both in vitro and in vivo, through lung capillaries, remained normal. Cancer cell growth within orthotopic implants and DNA damage-induced growth arrest were also insensitive to downregulated lamin A/C expression. Experimental lung metastasis of lamin A/C low cancer cells, however, was markedly reduced. Taken together, our results suggest that reduced lamin A/C expression increases nuclear squeezing through rigid confinements, does not impact intrinsic cancer cell growth and migration, but impairs metastatic survival in lungs