期刊
CANCERS
卷 13, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cancers13102383
关键词
cancer metastasis; nucleus; diapedesis; extravasation; epigenetics; chemotaxis; imaging
类别
资金
- Israel Science Foundation [791/17]
- Minerva Stiftung, GIF [I-1470-412.13/2018]
- EU Horizon 2020 Research and Innovation Program [RiboMed 857119]
- Moross Integrated Cancer Center
- Yeda-Sela Center for Basic Research
- Helen and Martin Kimmel Institute for Stem Cell Research
- Meyer Henri Cancer Endowment
- Israel Cancer Association [20201181]
Research indicates that reduced levels of A-type lamins in highly metastatic cancer cells do not increase their ability to pass through endothelial barriers and lung vessels, but may instead compromise lung metastasis at a later stage.
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. 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.
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