The mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using 2D substrates, much less is known about it in a physiologically more relevant 3D context. Here it is demonstrated that breast cancer tumor spheroids, growing in 3D polyethylene glycol-heparin hydrogels, are sensitive to their environment stiffness. During tumor spheroid growth, compressive stresses of up to 2 kPa build up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy reveals that tumor spheroid stiffness increases with hydrogel stiffness. Also, constituent cell stiffness increases in a Rho associated kinase (ROCK)- and F-actin-dependent manner. Increased hydrogel stiffness correlated with attenuated tumor spheroid growth, a higher proportion of cells in G0/G1 phase, and elevated levels of the cyclin-dependent kinase inhibitor p21. Drug-mediated ROCK inhibition not only reverses cell stiffening upon culture in stiff hydrogels but also increases tumor spheroid growth. Taken together, a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment is revealed here. Thus, the findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments.
|Published - 24 Jul 2019
Sustainable Development Goals
- Acrylic Resins/chemistry, Actins/genetics, Biomechanical Phenomena, Cell Culture Techniques, Cell Proliferation/drug effects, Cyclin-Dependent Kinase Inhibitor p21/genetics, Female, G1 Phase Cell Cycle Checkpoints/genetics, Gene Expression Regulation, Neoplastic, Heparin/chemistry, Humans, Hydrogels/chemical synthesis, MCF-7 Cells, Mechanotransduction, Cellular/genetics, Polyethylene Glycols/chemistry, Single-Cell Analysis/methods, Spheroids, Cellular/drug effects, Tumor Microenvironment/drug effects, rho-Associated Kinases/genetics