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

• Main Authors: Francesco Roncato, Ofer Regev, Sara W. Feigelson, Sandeep Kumar Yadav, Lukasz Kaczmarczyk, Nehora Levi, Diana Drago-Garcia, Samuel Ovadia, Marina Kizner, Yoseph Addadi, João C. Sabino, Yossi Ovadya, Sérgio F. de Almeida, Ester Feldmesser, Gabi Gerlitz, Ronen Alon
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Cancers
• Subjects: cancer metastasis; nucleus; diapedesis; extravasation; epigenetics; chemotaxis
• Online Access: https://www.mdpi.com/2072-6694/13/10/2383

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 <i>Yap1</i>. 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.