3D matrix adhesion feedback controls nuclear force coupling to drive invasive cell migration
Daniel Newman,
Lorna E. Young,
Thomas Waring,
Louise Brown,
Katarzyna I. Wolanska,
Ewan MacDonald,
Arthur Charles-Orszag,
Benjamin T. Goult,
Patrick T. Caswell,
Tetsushi Sakuma,
Takashi Yamamoto,
Laura M. Machesky,
Mark R. Morgan,
Tobias Zech
Affiliations
Daniel Newman
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Lorna E. Young
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Thomas Waring
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Louise Brown
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Katarzyna I. Wolanska
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Ewan MacDonald
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Arthur Charles-Orszag
CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, UK
Benjamin T. Goult
School of Biosciences, University of Kent, Canterbury, UK
Patrick T. Caswell
Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
Tetsushi Sakuma
Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8526, Japan
Takashi Yamamoto
Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8526, Japan
Laura M. Machesky
CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, UK; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, UK
Mark R. Morgan
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK
Tobias Zech
Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, UK; Corresponding author
Summary: Cell invasion is a multi-step process, initiated by the acquisition of a migratory phenotype and the ability to move through complex 3D extracellular environments. We determine the composition of cell-matrix adhesion complexes of invasive breast cancer cells in 3D matrices and identify an interaction complex required for invasive migration. βPix and myosin18A (Myo18A) drive polarized recruitment of non-muscle myosin 2A (NM2A) to adhesion complexes at the tips of protrusions. Actomyosin force engagement then displaces the Git1-βPix complex from paxillin, establishing a feedback loop for adhesion maturation. We observe active force transmission to the nucleus during invasive migration that is needed to pull the nucleus forward. The recruitment of NM2A to adhesions creates a non-muscle myosin isoform gradient, which extends from the protrusion to the nucleus. We postulate that this gradient facilitates coupling of cell-matrix interactions at the protrusive cell front with nuclear movement, enabling effective invasive migration and front-rear cell polarity.
