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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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/81048 |
| _version_ | 1828010551160078336 |
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| author | Carly M Krull Haiyi Li Amit Pathak |
| author_facet | Carly M Krull Haiyi Li Amit Pathak |
| author_sort | Carly M Krull |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-10T09:00:48Z |
| format | Article |
| id | doaj.art-335368f0f47a4dbda0ead17abaf3e99a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T09:00:48Z |
| publishDate | 2023-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-335368f0f47a4dbda0ead17abaf3e99a2023-02-21T12:30:43ZengeLife Sciences Publications LtdeLife2050-084X2023-02-011210.7554/eLife.81048Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epitheliaCarly M Krull0https://orcid.org/0000-0002-8170-4282Haiyi Li1Amit Pathak2https://orcid.org/0000-0003-4006-5119Department of Biomedical Engineering, Washington University in St. Louis, St Louis, United StatesDepartment of Computer Science and Engineering, Washington University in St. Louis, St Louis, United StatesDepartment of Biomedical Engineering, Washington University in St. Louis, St Louis, United States; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St Louis, United StatesDynamic 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.https://elifesciences.org/articles/81048epithelial cellsnuclear exportnucleocytoplasmic transportepithelial–mesenchymal transitionEMTmechanobiology |
| spellingShingle | Carly M Krull Haiyi Li Amit Pathak Nuclear export inhibition jumbles epithelial–mesenchymal states and gives rise to migratory disorder in healthy epithelia eLife epithelial cells nuclear export nucleocytoplasmic transport epithelial–mesenchymal transition EMT mechanobiology |
| 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 | epithelial cells nuclear export nucleocytoplasmic transport epithelial–mesenchymal transition EMT mechanobiology |
| url | https://elifesciences.org/articles/81048 |
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