Kim, Jin-Hong and Asthagiri, Anand R. (2011) Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation. Journal of Cell Science, 124 (8). pp. 1280-1287. ISSN 0021-9533 http://resolver.caltech.edu/CaltechAUTHORS:20110414-085411588
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Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.
|Additional Information:||© 2011 Published by The Company of Biologists Ltd. Accepted 17 December 2010. First published online 23 March 2011. We thank D. Shen for help with image analysis, the Caltech Biological Imaging Center for access to a confocal microscope, and J. Notbohm and G. Ravichandran for help in mechanical characterization of polyacrylamide gels. This work was supported by the NCI-USC Physical Sciences of Oncology Center (U54CA143907) and the Jacobs Foundation at Caltech. Deposited in PMC for release after 12 months.|
|Subject Keywords:||Cancer; Contact inhibition; Matrix stiffness; Proliferation; Mechanotransduction|
|Official Citation:||Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation J Cell Sci Kim and Asthagiri 124: 1280|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Ruth Sustaita|
|Deposited On:||19 Apr 2011 17:03|
|Last Modified:||19 Apr 2011 17:03|
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