The Effect of Geometry and TGF-β Signaling on Tumor Cell Migration from Free-Standing Microtissues
Abstract
Recapitulation of 3D multicellular tissues in vitro is of great interest to the field of tumor biology to study the integrated effect of local biochemical and biophysical signals on tumor cell migration and invasion. However, most microengineered tissues and spheroids are unable to recapitulate in vitro the complexities of 3D geometries found in vivo. Here, lithographically defined degradable alginate microniches are presented to produce free-standing tumor microtissues, with precisely controlled geometry, high viability, and allowing for high cell proliferation. The role of microtissue geometry and TGF-β signaling in tumor cell migration is further investigated. TGF-β is found to induce the expression of p-myosin II, vimentin, and YAP/TAZ nuclear localization at the periphery of the microtissue, where enhanced nuclear stiffness and orientation are also observed. Upon embedding in a collagen matrix, microtissues treated with TGF-β maintain their geometric integrity, possibly due to the higher cell tension observed around the periphery. In contrast, cells in microtissues not treated with TGF-β are highly mobile and invade the surrounding matrix rapidly, with the initial migration strongly dependent on the local geometry. The microtissues presented here are promising model systems for studying the influence of biophysical properties and soluble factors on tumor cell migration.
Additional Information
© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Issue Online: 22 June 2022; Version of Record online: 25 February 2022; Accepted manuscript online: 19 February 2022; Manuscript revised: 11 February 2022; Manuscript received: 17 January 2022. The authors thank Manon Bertrand for the tests of different cell lines; the authors also thank Baoxiu Wang for the assistance of alginate gels optimization. The authors are grateful to the Department of General Instruments of Radboud University for providing Leica Sp8 confocal microscopy services. The authors would like to acknowledge Prof. Joachim Spatz for the support of TGF-β regulation experiments by providing TGF-β, MDA-MB-231 cells, and antibodies for vimentin, Lamin A/C and YAP/TAZ staining, which were performed in the department of cellular biophysics, Max Planck Institute for medical research, Germany. J.X. also acknowledges financial support from the China Scholarship Council and the Max Planck Institute. Author contributions: W.T.S.H. proposed this project; W.T.S.H., M.B., and J.X. planned and designed experiments; J.X. and X.H. performed experiments; A.P. prepared silicon masks; L.C. and Z.Z. contributed to the synthesis of RGD-Alg; J.X. analyzed data and wrote the manuscript; J.X., M.B., and W.T.S.H. revised the manuscript. The authors declare no conflict of interest. Data Availability Statement: The data that support the findings of this study are available in the supplementary material of this article.Attached Files
Supplemental Material - adhm202102696-sup-0001-suppmat.pdf
Supplemental Material - adhm202102696-sup-0002-videos1.avi
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Additional details
- Eprint ID
- 113535
- DOI
- 10.1002/adhm.202102696
- Resolver ID
- CaltechAUTHORS:20220222-707146000
- China Scholarship Council
- Max Planck Institute for Medical Research
- Created
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2022-02-23Created from EPrint's datestamp field
- Updated
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2022-07-12Created from EPrint's last_modified field