10th Annual Symposium
Physics of Cancer
Leipzig, Germany
September 25-27, 2019
Invited Talk
3D microenvironment stiffness regulates tumor spheroid growth and mechanics via p21 and ROCK
Anna V. Taubenberger1, Salvatore Girardo1,3, Nicole Träber1,2, Elisabeth Fischer-Friedrich1, Martin Kräter1,3, Katrin Wagner1, Thomas Kurth1, Isabel Richter1, Barbara Haller1, Marcus Binner2, Dominik Hahn2, Uwe Freudenberg2, Carsten Werner1,2, Jochen Guck1,3
1TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307 Dresden, Germany
2Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069 Dresden, Germany
3Max Planck Institute for the Science of Light, Max-Planck-Zentrum für Physik und Medizin, Staudtstr. 2, 91058 Erlangen, Germany
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Mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using two-dimensional (2D) substrates, much less is known about it in a physiologically more relevant 3D context. Here we demonstrate 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 built up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy (AFM) revealed that tumor spheroid stiffness increased with hydrogel stiffness. Also, constituent cell stiffness increased in a 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 reversed not only cell stiffening upon culture in stiff hydrogels but also increased tumor spheroid growth. Taken together, we reveal here a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment. Thus, our findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments and provide the basis for a more in-depth exploration of the underlying mechanosensory response.
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