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Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement

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 interac...

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Autores principales: Law, Robert A., Kiepas, Alexander, Desta, Habben E., Perez Ipiña, Emiliano, Parlani, Maria, Lee, Se Jong, Yankaskas, Christopher L., Zhao, Runchen, Mistriotis, Panagiotis, Wang, Nianchao, Gu, Zhizhan, Kalab, Petr, Friedl, Peter, Camley, Brian A., Konstantopoulos, Konstantinos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9833664/
https://www.ncbi.nlm.nih.gov/pubmed/36630496
http://dx.doi.org/10.1126/sciadv.abq6480
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author Law, Robert A.
Kiepas, Alexander
Desta, Habben E.
Perez Ipiña, Emiliano
Parlani, Maria
Lee, Se Jong
Yankaskas, Christopher L.
Zhao, Runchen
Mistriotis, Panagiotis
Wang, Nianchao
Gu, Zhizhan
Kalab, Petr
Friedl, Peter
Camley, Brian A.
Konstantopoulos, Konstantinos
author_facet Law, Robert A.
Kiepas, Alexander
Desta, Habben E.
Perez Ipiña, Emiliano
Parlani, Maria
Lee, Se Jong
Yankaskas, Christopher L.
Zhao, Runchen
Mistriotis, Panagiotis
Wang, Nianchao
Gu, Zhizhan
Kalab, Petr
Friedl, Peter
Camley, Brian A.
Konstantopoulos, Konstantinos
author_sort Law, Robert A.
collection PubMed
description 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.
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spelling pubmed-98336642023-01-18 Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement Law, Robert A. Kiepas, Alexander Desta, Habben E. Perez Ipiña, Emiliano Parlani, Maria Lee, Se Jong Yankaskas, Christopher L. Zhao, Runchen Mistriotis, Panagiotis Wang, Nianchao Gu, Zhizhan Kalab, Petr Friedl, Peter Camley, Brian A. Konstantopoulos, Konstantinos Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2023-01-11 /pmc/articles/PMC9833664/ /pubmed/36630496 http://dx.doi.org/10.1126/sciadv.abq6480 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Law, Robert A.
Kiepas, Alexander
Desta, Habben E.
Perez Ipiña, Emiliano
Parlani, Maria
Lee, Se Jong
Yankaskas, Christopher L.
Zhao, Runchen
Mistriotis, Panagiotis
Wang, Nianchao
Gu, Zhizhan
Kalab, Petr
Friedl, Peter
Camley, Brian A.
Konstantopoulos, Konstantinos
Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title_full Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title_fullStr Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title_full_unstemmed Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title_short Cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
title_sort cytokinesis machinery promotes cell dissociation from collectively migrating strands in confinement
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9833664/
https://www.ncbi.nlm.nih.gov/pubmed/36630496
http://dx.doi.org/10.1126/sciadv.abq6480
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