Journal
CONVERGENT SCIENCE PHYSICAL ONCOLOGY
Volume 3, Issue 4, Pages -Publisher
IOP PUBLISHING LTD
DOI: 10.1088/2057-1739/aa8bbb
Keywords
nanobiophysics; human breast cancer cells; invasiveness and metastasis; contractile forces; cell mechanics
Categories
Funding
- Deutsche Forschungsgemeinschaft [MI1211/18-1, INST258/357-1FUGG]
- ESF-SAB [100146227]
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Cellular motility and invasion in connective tissue is a basic and fundamental process during normal physiological tissue developments and assemblies, prevention of inflammation after tissue injury through wound healing and malignant progression of cancer such as metastasis. Cell invasion usually requires cell adhesion via cell-matrix receptors to the extracellular matrix which are coupled to the cell's actomyosin cytoskeleton. In many tumors, matrix and hence tissue mechanics are altered and increased tissue stiffness is associated with increased malignancy and metastasis. Moreover, cellular mechanical properties are altered in invasive cancer cells compared to less invasive cancer cells. Here, we have studied the invasion of human breast cancer cells into loose and dense 3D engineered matrices consisting of a collagen type I fiber network and determined the cellular mechanical properties such as stiffness. As expected, the cellular stiffness correlates with the invasiveness of the cancer cells in loose and dense 3D matrices. We hypothesized that the matrix and cellular mechanical properties regulate the motility (invasiveness) of cancer cells in 3D engineered matrices, which has been shown to be to be regulated by the actomyosin cytoskeleton and is in 3D constrictions possibly also regulated by the small Rho GTPase Rac1's activity as demonstrated for cellular motility on 2D substrates. Pharmacological interventions indicate that in 3D matrices, invasive cancer cells behave similarly as non-invasive cancer cells, when treated with inhibitors of the small Rho GTPase Rac1 or the actomyosin-contractility. Matrix fiber displacement analysis in 3D engineered matrices revealed that the invasive MDA-MB-231 cancer cells generated significantly higher and long-raged matrix fiber displacements by contraction of the matrix environment than non-invasive MCF-7 and MCF-10A breast cancer cells, which seems to be the main prerequisite for their increased invasion through the 3D extracellular matrix environment. In addition, a decrease in adhesion-dependent and adhesion-independent cellular stiffness of invasive MDA-MB-231 cancer cells after addition of the actin polymerization inhibitor Latrunculin A leads to reduced 3D invasiveness and significantly reduced matrix fiber displacements. Besides cellular mechanical properties, a 18-fold increase in matrix stiffness increased the invasiveness of all three cell types suggesting that matrix stiffness may have an invasion-enhancing effect. Finally, our findings demonstrate that mechanical properties of breast cancer cells and the 3D matrix environment facilitate 3D matrix invasion through increased actomyosin-dependent cellular stiffness and transmission of contractile force in dense 3D engineered collagen matrices.
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