RT Journal Article
SR Electronic
T1 3D matrix adhesion composition facilitates nuclear force coupling to drive invasive cell migration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.17.443835
DO 10.1101/2021.05.17.443835
A1 Daniel Newman
A1 Lorna Young
A1 Thomas Waring
A1 Louise Brown
A1 Katarzyna Wolanska
A1 Ewan Macdonald
A1 Arthur Charles Orszag
A1 Patrick Caswell
A1 Tetsushi Sakuma
A1 Takashi Yamamoto
A1 Laura Machesky
A1 Mark Morgan
A1 Tobias Zech
YR 2021
UL http://biorxiv.org/content/early/2021/05/17/2021.05.17.443835.abstract
AB Cell invasion and metastasis is a multi-step process, initialised through the acquisition of a migratory phenotype and the ability to move through differing and complex 3D extracellular environments. In this study we set out to identify the parameters required for invasive cell migration in 3D environments. Cells interact with the extracellular matrix via transmembrane-spanning integrin adhesion complexes, which are well characterised in cells plated on 2D surfaces, yet much less is known about them in cells embedded in 3D matrices. We establish a technique to determine the composition of cell matrix adhesion complexes of invasive breast cancer cells in 3D matrices and on 2D surfaces and we identify an interaction complex enriched in 3D adhesive sites required for 3D invasive migration. Depletion of β-PIX-Myosin18A (Myo18A) abolishes cancer cell invasion, without negatively affecting matrix degradation, Rho GTPase signalling, or protrusion formation in collagen matrices. Instead, in a mechanism only seen in cells moving through 3D matrix, β-PIX and Myo18A drive the polarised recruitment of non-muscle Myosin 2A (NM2A) to the tips of protrusions. This recruitment of NM2A is required for the creation of an NM2A-NM2B isoform gradient, which ranges from the protrusion to the nucleus. We observe a requirement for active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. We postulate that the establishment of the NM2A-NM2B actomyosin gradient facilitates the coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity.Competing Interest StatementThe authors have declared no competing interest.