Reduced Lamin A/C Does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

SIMPLE SUMMARY: The nucleus is the largest and stiffest organelle of tumor cells. Cancer metastasis depends on the ability of cancer cells circulating in the blood to exit blood vessels and survive in target organs. The roles of the shell (lamina) of the nucleus in cancer cell migration and survival in distinct organs of metastasis are still unclear. A-type lamins are key lamina components that increase nuclear stiffness and reduce squeezing capacity through highly rigid barriers. We addressed how reduced expression of A-lamins (lamin A/C) affects cancer cell survival and crossing of endothelial barriers and lung capillaries and found that reduced lamin A/C expression impairs cancer growth in spheroids and restricts cancer metastasis to lungs without improving cancer cell squeezing and extravasation from lung vessels, the key platform for cancer entry into lungs. ABSTRACT: The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.