7th Annual Symposium
Physics of Cancer
October 4-6, 2016
|PoC - Physics of Cancer - Annual Symposium|
Matrix adhesion sites drive 3D cancer cell migration through direct force coupling to the nucleus
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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.