8th Annual Symposium
Physics of Cancer
October 4-6, 2017
|PoC - Physics of Cancer - Annual Symposium|
Matrix adhesion site function in polarised invasive migration
Contact: | Website
The nucleus is a major constraint on the ability of cells to migrate through dense 3D matrix. In order to progress cells must actively translocate their nuclei through restrictive pores present in the dense extracellular matrix. Using a Nesprin2 based FRET/FLIM biosensor we demonstrate that the nuclei of cells migrating through dense 3D matrices experience greater actomyosin mediated tension in comparison to cells in a less dense or 2D matrix. Further 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 examine the mechanisms responsible for the generation of polarised nuclear tension that is required for 3D invasive cell migration. Cancer cells migrating through dense 3D matrices form actin rich degradative adhesion sites, which share properties of both focal adhesions and invadopodia. Using novel proximity labelling (BioID) based interaction screens we have identified a novel interaction module consisting of N-WASP/WIP -> ARHGEF7 -> Myosin18 that is present in invasive 3D adhesion sites. While the loss of this interaction module does not impede protrusion dynamics or matrix degradation, it is essential for differential localisation of non-muscle MyosinIIa (NMIIa) and non-muscle MyosinIIb (NMII2b) at adhesion sites at the protrusive front of the cell and the perinuclear region of cells cancer cells, respectively. The workload difference of NMIIa and NMIIb has the potential to generate contraction force gradients along actomyosin fibers in migrating cells. ARHGEF7 and Myosin18a are therefore essential for the generation of a force gradient from adhesions sites at the leading edge to the nucleus that is required for front–rear polarity of migrating cells. This leads us to hypothesise that actin based nuclear force coupling from adhesion sites in the foundation of polarity in migration and adhesion based cellular motility in 3D matrix.