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3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK.
Adv Biosyst. 2019 09; 3(9):e1900128.AB

Abstract

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.

Authors+Show Affiliations

TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany. Max Planck Institute for the Science of Light, Max-Planck-Zentrum für Physik und Medizin, Staudtstr. 2, 91058, Erlangen, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany. Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany. Max Planck Institute for the Science of Light, Max-Planck-Zentrum für Physik und Medizin, Staudtstr. 2, 91058, Erlangen, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany.Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069, Dresden, Germany.Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069, Dresden, Germany.Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany. Leibniz Institute of Polymer Research Dresden, Max Bergmann Center, Hohe Str. 6, 01069, Dresden, Germany.TU Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Fetscherstr. 105, 01307, Dresden, Germany. Max Planck Institute for the Science of Light, Max-Planck-Zentrum für Physik und Medizin, Staudtstr. 2, 91058, Erlangen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32648654

Citation

Taubenberger, Anna V., et al. "3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics Via P21 and ROCK." Advanced Biosystems, vol. 3, no. 9, 2019, pp. e1900128.
Taubenberger AV, Girardo S, Träber N, et al. 3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK. Adv Biosyst. 2019;3(9):e1900128.
Taubenberger, A. V., Girardo, S., Träber, N., Fischer-Friedrich, E., Kräter, M., Wagner, K., Kurth, T., Richter, I., Haller, B., Binner, M., Hahn, D., Freudenberg, U., Werner, C., & Guck, J. (2019). 3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK. Advanced Biosystems, 3(9), e1900128. https://doi.org/10.1002/adbi.201900128
Taubenberger AV, et al. 3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics Via P21 and ROCK. Adv Biosyst. 2019;3(9):e1900128. PubMed PMID: 32648654.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK. AU - Taubenberger,Anna V, AU - Girardo,Salvatore, AU - Träber,Nicole, AU - Fischer-Friedrich,Elisabeth, AU - Kräter,Martin, AU - Wagner,Katrin, AU - Kurth,Thomas, AU - Richter,Isabel, AU - Haller,Barbara, AU - Binner,Marcus, AU - Hahn,Dominik, AU - Freudenberg,Uwe, AU - Werner,Carsten, AU - Guck,Jochen, Y1 - 2019/07/24/ PY - 2019/06/03/received PY - 2020/7/11/entrez PY - 2020/7/11/pubmed PY - 2020/7/11/medline KW - 3D culture KW - atomic force microscopy KW - cell mechanics KW - compression KW - stress sensor KW - tumor microenvironment KW - tumor spheroid SP - e1900128 EP - e1900128 JF - Advanced biosystems JO - Adv Biosyst VL - 3 IS - 9 N2 - 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. SN - 2366-7478 UR - https://www.unboundmedicine.com/medline/citation/32648654/3D_Microenvironment_Stiffness_Regulates_Tumor_Spheroid_Growth_and_Mechanics_via_p21_and_ROCK L2 - https://antibodies.cancer.gov/detail/CPTC-PCNA-3 DB - PRIME DP - Unbound Medicine ER -
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