Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement

Robert A Law; Alexander Kiepas; Habben E Desta; Emiliano Perez Ipiña; Maria Parlani; Se Jong Lee; Christopher L Yankaskas; Runchen Zhao; Panagiotis Mistriotis; Nianchao Wang; Zhizhan Gu; Petr Kalab; Peter Friedl; Brian A Camley; Konstantinos Konstantopoulos

doi:10.1126/sciadv.abq6480

Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement

Sci Adv. 2023 Jan 13;9(2):eabq6480. doi: 10.1126/sciadv.abq6480. Epub 2023 Jan 11.

Authors

Robert A Law^{1

2}, Alexander Kiepas^{1

2}, Habben E Desta^{1

2}, Emiliano Perez Ipiña³, Maria Parlani⁴, Se Jong Lee^{1

2}, Christopher L Yankaskas^{1

2}, Runchen Zhao^{1

2}, Panagiotis Mistriotis^{1

2

5}, Nianchao Wang^{1

2}, Zhizhan Gu^{1

2}, Petr Kalab¹, Peter Friedl^{4

6

7}, Brian A Camley^{3

8}, Konstantinos Konstantopoulos^{1

2

9

10}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
² Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
³ William H. Miller III Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
⁶ Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁷ Cancer Genomics Center, 3584 Utrecht, Netherlands.
⁸ Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.
⁹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
¹⁰ Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.

Abstract

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.

MeSH terms

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

Substances

Cadherins
Rho Guanine Nucleotide Exchange Factors

Abstract

MeSH terms

Substances

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