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Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia

Dynamic nucleocytoplasmic transport of E-M factors regulates cellular E-M states; yet, it remains unknown how simultaneously trapping these factors affects epithelia at the macroscale. To explore this question, we performed nuclear export inhibition (NEI) via leptomycin B and Selinexor treatment, wh...

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Detalles Bibliográficos
Autores principales: Krull, Carly M, Li, Haiyi, Pathak, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943065/
https://www.ncbi.nlm.nih.gov/pubmed/36805020
http://dx.doi.org/10.7554/eLife.81048
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author Krull, Carly M
Li, Haiyi
Pathak, Amit
author_facet Krull, Carly M
Li, Haiyi
Pathak, Amit
author_sort Krull, Carly M
collection PubMed
description Dynamic nucleocytoplasmic transport of E-M factors regulates cellular E-M states; yet, it remains unknown how simultaneously trapping these factors affects epithelia at the macroscale. To explore this question, we performed nuclear export inhibition (NEI) via leptomycin B and Selinexor treatment, which biases nuclear localization of CRM1-associated E-M factors. We examined changes in collective cellular phenotypes across a range of substrate stiffnesses. Following NEI, soft substrates elevate collective migration of MCF10A cells for up to 24 hr, while stiffer substrates reduce migration at all time points. Our results suggest that NEI disrupts migration through competition between intercellular adhesions and mechanoactivation, generally causing loss of cell–cell coordination. Specifically, across substrate stiffnesses, NEI fosters an atypical E-M state wherein MCF10A cells become both more epithelial and more mesenchymal. We observe that NEI fosters a range of these concurrent phenotypes, from more epithelial shYAP MCF10A cells to more mesenchymal MDCK II cells. α-Catenin emerges as a potential link between E-M states, where it maintains normal levels of intercellular adhesion and transmits mechanoactive characteristics to collective behavior. Ultimately, to accommodate the concurrent states observed here, we propose an expanded E-M model, which may help further understand fundamental biological phenomena and inform pathological treatments.
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spelling pubmed-99430652023-02-22 Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia Krull, Carly M Li, Haiyi Pathak, Amit eLife Physics of Living Systems Dynamic nucleocytoplasmic transport of E-M factors regulates cellular E-M states; yet, it remains unknown how simultaneously trapping these factors affects epithelia at the macroscale. To explore this question, we performed nuclear export inhibition (NEI) via leptomycin B and Selinexor treatment, which biases nuclear localization of CRM1-associated E-M factors. We examined changes in collective cellular phenotypes across a range of substrate stiffnesses. Following NEI, soft substrates elevate collective migration of MCF10A cells for up to 24 hr, while stiffer substrates reduce migration at all time points. Our results suggest that NEI disrupts migration through competition between intercellular adhesions and mechanoactivation, generally causing loss of cell–cell coordination. Specifically, across substrate stiffnesses, NEI fosters an atypical E-M state wherein MCF10A cells become both more epithelial and more mesenchymal. We observe that NEI fosters a range of these concurrent phenotypes, from more epithelial shYAP MCF10A cells to more mesenchymal MDCK II cells. α-Catenin emerges as a potential link between E-M states, where it maintains normal levels of intercellular adhesion and transmits mechanoactive characteristics to collective behavior. Ultimately, to accommodate the concurrent states observed here, we propose an expanded E-M model, which may help further understand fundamental biological phenomena and inform pathological treatments. eLife Sciences Publications, Ltd 2023-02-21 /pmc/articles/PMC9943065/ /pubmed/36805020 http://dx.doi.org/10.7554/eLife.81048 Text en © 2023, Krull et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Physics of Living Systems
Krull, Carly M
Li, Haiyi
Pathak, Amit
Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title_full Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title_fullStr Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title_full_unstemmed Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title_short Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
title_sort nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia
topic Physics of Living Systems
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943065/
https://www.ncbi.nlm.nih.gov/pubmed/36805020
http://dx.doi.org/10.7554/eLife.81048
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AT lihaiyi nuclearexportinhibitionjumblesepithelialmesenchymalstatesandgivesrisetomigratorydisorderinhealthyepithelia
AT pathakamit nuclearexportinhibitionjumblesepithelialmesenchymalstatesandgivesrisetomigratorydisorderinhealthyepithelia