The migration and invasion of cancer cells through 3D confined extracellular matrices
is coupled to cell mechanics and the mechanics of the extracellular matrix. Cell
mechanics is mainly determined by both the mechanics of the largest organelle in
the cell, the nucleus, and the cytoskeletal architecture of the cell. Hence, cytoskeletal
and nuclear mechanics are the major contributors to cell mechanics. Among other
factors, steric hindrances of the extracellular matrix confinement are supposed to affect
nuclear mechanics and thus also influence cell mechanics. Therefore, we propose that
the percentage of invasive cells and their invasion depths into loose and dense 3D
extracellular matrices is regulated by both nuclear and cytoskeletal mechanics. In order
to investigate the effect of both nuclear and cytoskeletal mechanics on the overall
cell mechanics, we firstly altered nuclear mechanics by the chromatin de-condensing
reagent Trichostatin A (TSA) and secondly altered cytoskeletal mechanics by addition
of actin polymerization inhibitor Latrunculin A and the myosin inhibitor Blebbistatin. In
fact, we found that TSA-treated MDA-MB-231 human breast cancer cells increased
their invasion depth in dense 3D extracellular matrices, whereas the invasion depths
in loose matrices were decreased. Similarly, the invasion depths of TSA-treated MCF-
7 human breast cancer cells in dense matrices were significantly increased compared
to loose matrices, where the invasion depths were decreased. These results are also
valid in the presence of a matrix-metalloproteinase inhibitor GM6001. Using atomic
force microscopy (AFM), we found that the nuclear stiffnesses of both MDA-MB-
231 and MCF-7 breast cancer cells were pronouncedly higher than their cytoskeletal
stiffness, whereas the stiffness of the nucleus of human mammary epithelial cells was
decreased compared to their cytoskeleton. TSA treatment reduced cytoskeletal and
nuclear stiffness of MCF-7 cells, as expected. However, a softening of the nucleus by
TSA treatment may induce a stiffening of the cytoskeleton of MDA-MB-231 cells and
subsequently an apparent stiffening of the nucleus. Inhibiting actin polymerization using
Latrunculin A revealed a softer nucleus of MDA-MB-231 cells under TSA treatment. This
indicates that the actin-dependent cytoskeletal stiffness seems to be influenced by the
TSA-induced nuclear stiffness changes. Finally, the combined treatment with TSA and
Latrunculin A further justifies the hypothesis of apparent nuclear stiffening, indicating that
cytoskeletal mechanics seem to be regulated by nuclear mechanics.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84503 |
| Date | 03 April 2023 |
| Creators | Fischer, Tony, Hayn, Alexander, Mierke, Claudia Tanja |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2296-634X, 393 |
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