Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement.

Cadherins / metabolism Cytokinesis / physiology Intercellular Junctions / metabolism Microtubules / metabolism Rho Guanine Nucleotide Exchange Factors / genetics Humans

Journal

Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440

Informations de publication

Date de publication:
13 01 2023
Historique:
entrez: 11 1 2023
pubmed: 12 1 2023
medline: 14 1 2023
Statut: ppublish

Résumé

Cells tune adherens junction dynamics to regulate epithelial integrity in diverse (patho)physiological processes, including cancer metastasis. We hypothesized that the spatially confining architecture of peritumor stroma promotes metastatic cell dissemination by remodeling cell-cell adhesive interactions. By combining microfluidics with live-cell imaging, FLIM/FRET biosensors, and optogenetic tools, we show that confinement induces leader cell dissociation from cohesive ensembles. Cell dissociation is triggered by myosin IIA (MIIA) dismantling of E-cadherin cell-cell junctions, as recapitulated by a mathematical model. Elevated MIIA contractility is controlled by RhoA/ROCK activation, which requires distinct guanine nucleotide exchange factors (GEFs). Confinement activates RhoA via nucleocytoplasmic shuttling of the cytokinesis-regulatory proteins RacGAP1 and Ect2 and increased microtubule dynamics, which results in the release of active GEF-H1. Thus, confining microenvironments are sufficient to induce cell dissemination from primary tumors by remodeling E-cadherin cell junctions via the interplay of microtubules, nuclear trafficking, and RhoA/ROCK/MIIA pathway and not by down-regulating E-cadherin expression.

Identifiants

DOI: 10.1126/sciadv.abq6480 PMID: 36630496 PMC: PMC9833664
pubmed: 36630496
doi: 10.1126/sciadv.abq6480
pmc: PMC9833664
doi:

Substances chimiques

Cadherins 0
Rho Guanine Nucleotide Exchange Factors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

eabq6480

Subventions

Organisme : NIGMS NIH HHS
ID : R35 GM142847
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM147101
Pays : United States

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Auteurs

Robert A Law (RA)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-2904-4889

Alexander Kiepas (A)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0001-8169-3897

Habben E Desta (HE)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-0328-9597

Emiliano Perez Ipiña (E)

William H. Miller III Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-1664-0411

Maria Parlani (M)

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
ORCID: 0000-0002-2901-5527

Se Jong Lee (SJ)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.

Christopher L Yankaskas (CL)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-9102-4213

Runchen Zhao (R)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0001-8673-3990

Panagiotis Mistriotis (P)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
ORCID: 0000-0002-8069-3278

Nianchao Wang (N)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.

Zhizhan Gu (Z)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0001-9934-5209

Petr Kalab (P)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-8145-7728

Peter Friedl (P)

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Cancer Genomics Center, 3584 Utrecht, Netherlands.
ORCID: 0000-0002-0119-4041

Brian A Camley (BA)

William H. Miller III Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.
ORCID: 0000-0002-0765-6956

Konstantinos Konstantopoulos (K)

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
ORCID: 0000-0003-2623-1459

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Classifications MeSH

questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › Cadhérines › Cytokinesis machinery promotes cell...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › Cytocinèse › Cytokinesis machinery promotes cell...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Cytokinesis machinery promotes cell...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Cytosquelette › Microtubules › Cytokinesis machinery promotes cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › Rho guanine nucleotide exchange factors › Cytokinesis machinery promotes cell...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Cytokinesis machinery promotes cell...