Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization

Rudzka, D. A. et al. (2019) Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization. Journal of Cell Science, 132(11), jcs224071. (doi: 10.1242/jcs.224071) (PMID:31152052) (PMCID:PMC6589089)

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Abstract

Cancer cells are softer than the normal cells, and metastatic cells are even softer. These changes in biomechanical properties contribute to cancer progression by facilitating cell movement through physically constraining environments. To identify properties that enabled passage through physical constraints, cells that were more efficient at moving through narrow membrane micropores were selected from established cell lines. By examining micropore-selected human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, membrane fluidity and nuclear elasticity were excluded as primary contributors. Instead, reduced actin cytoskeleton anisotropy, focal adhesion density and cell stiffness were characteristics associated with efficient passage through constraints. By comparing transcriptomic profiles between the parental and selected populations, increased Ras/MAPK signalling was linked with cytoskeleton rearrangements and cell softening. MEK inhibitor treatment reversed the transcriptional, cytoskeleton, focal adhesion and elasticity changes. Conversely, expression of oncogenic KRas in parental MDA MB 231 cells, or oncogenic BRaf in parental MDA MB 435 cells, significantly reduced cell stiffness. These results reveal that MAPK signalling, in addition to tumour cell proliferation, has a significant role in regulating cell biomechanics.

Item Type:Articles
Additional Information:Also funded by Cancer Research UK (A18276 and A17196).
Keywords:Cytoskeleton, elasticity, MAPK, motility.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Munro, Dr June and Yin, Professor Huabing and Spennati, Giulia and Blyth, Professor Karen and Kalna, Dr Gabriela and Neilson, Dr Matthew and Rudzka, Dr Dominika and Mason, Miss Susan and Mullin, Mrs Margaret and Olson, Professor Michael
Authors: Rudzka, D. A., Spennati, G., McGarry, D. J., Chim, Y.-H., Neilson, M., Ptak, A., Munro, J., Kalna, G., Hedley, A., Moralli, D., Green, C., Mason, S., Blyth, K., Mullin, M., Yin, H., and Olson, M. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering > School of Engineering
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Journal of Cell Science
Publisher:Company of Biologists
ISSN:0021-9533
ISSN (Online):1477-9137
Published Online:31 May 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of Cell Science 132(11):jcs224071
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
682111Cysteine oxidation as a regulator of cancer cell motility and invasionMichael OlsonMedical Research Council (MRC)MR/M018776/1ICS - BEATSON INSTITUTE FOR CANCER RES.
694461EPSRC Centre for Multiscale soft tissue mechanics with application to heart & cancerRaymond OgdenEngineering and Physical Sciences Research Council (EPSRC)EP/N014642/1M&S - MATHEMATICS