7th Annual Symposium
Physics of Cancer
Leipzig, Germany
October 4-6, 2016
Contributed Talk
Matrix adhesion sites drive 3D cancer cell migration through direct force coupling to the nucleus
Tobias Zech1, Daniel Newman1, Iben Ronn-Vehland2, Vineetha Vijayakumar3, Gareth E. Jones3, Patrick T. Caswell4, Mark R. Morgan1, Laura M. Machesky2
1University of Liverpool, Institute of Translational Medicine, Cellular and Molecular Physiology, Crown Street, Liverpool, L69 3BX, UK
2The Beatson Institute for Cancer Research, Switchback, Rd., Bearsden, Glasgow, G61 1BD, UK
3King’s College London, Randall Division of Cell & Molecular Biophysics, London WC2R 2LS, UK
4University of Manchester,3Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, Manchester, M13 9PT, UK,
Contact:  | Website
The nucleus is a major constraint on cells migrating through a dense 3D matrix, as cells must actively squeeze their nuclei through matrix pores. Using a novel Nesprin-2 based FRET/FLIM force biosensor we provide the first indication that the nucleus is being actively pulled forward when cells migrate through 3D matrices in a Nesprin-2 dependant manner. This study set out to identify how cells pull their nuclei forward to achieve 3D invasive migration. Cancer cells invading into 3D matrices form adhesion structures, which share properties of focal/fibrillar adhesions and invadopodia. Using novel proximity labelling (BioID) based interaction screens of 3D matrix adhesion site composition we have identified a novel interaction module consisting of N-WASP/WIP -> ARHGEF7 -> Myosin18 that is present in invasive 3D adhesion sites. The disruption of this protein interaction module alters the force dynamics and composition of adhesion sites and concomitantly inhibits nuclear force coupling required for effective invasive migration, but did not affect protrusions dynamics or matrix degradation. Loss of nuclear force coupling –from either the adhesion or nuclear site- lead to a loss of polarised migration and tension dependant pro-invasive gene transcription by YAP/TAZ. This leads us to hypothesise that actin based nuclear force coupling from adhesion sites determines the axis of polarity in migration and is the basis of adhesion based cellular motility in 3D matrix.
University of Leipzig  |  Faculty of Physics and Earth Sciences  |  Institute of Experimental Physics I  |  Soft Matter Physics Division
© Soft Matter Physics Division, University of Leipzig. Designed and created by sp design. Imprint & Disclaimer