3D microenvironment stiffness regulates tumor spheroid growth and mechanics via p21 and ROCK
| Autor: | Katrin Wagner, Carsten Werner, Marcus Binner, Thomas Kurth, Anna Taubenberger, Jochen Guck, Dominik Hahn, Nicole Träber, Salvatore Girardo, Barbara Haller, Uwe Freudenberg, Elisabeth Fischer-Friedrich, Martin Kräter, Isabel Richter |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Tumor spheroid Cell Biomedical Engineering Acrylic Resins Cell Culture Techniques Context (language use) macromolecular substances Mechanotransduction Cellular General Biochemistry Genetics and Molecular Biology Polyethylene Glycols Biomaterials Spheroids Cellular medicine Tumor Microenvironment Humans Cytoskeleton Cell Proliferation Tumor microenvironment rho-Associated Kinases Chemistry Kinase Heparin technology industry and agriculture Stiffness Hydrogels equipment and supplies G1 Phase Cell Cycle Checkpoints Actins Biomechanical Phenomena Gene Expression Regulation Neoplastic medicine.anatomical_structure Self-healing hydrogels Cancer cell embryonic structures Biophysics MCF-7 Cells Female medicine.symptom Single-Cell Analysis |
| DOI: | 10.1101/586784 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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